Selectins and Associated Adhesion Proteins in Inflammatory disorders



Inflammation is defined as the normal response of living tissue to injury or infection. It is important to emphasize two components of this definition. First, that inflammation is a normal response and, as such, is expected to occur when tissue is damaged. Infact, if injured tissue does not exhibit signs of inflammation this would be considered abnormal and wounds and infections would never heal without inflammation. Secondly, inflammation occurs in living tissue, hence there is need for an adequate blood supply to the tissues in order to exhibit an inflammatory response. The inflammatory response may be triggered by mechanical injury, chemical toxins, and invasion by microorganisms, and hypersensitivity reactions. Three major events occur during the inflammatory response: the blood supply to the affected area is increased substantially, capillary permeability is increased, and leucocytes migrate from the capillary vessels into the surrounding interstitial spaces to the site of inflammation or injury. The inflammatory response represents a complex biological and biochemical process involving cells of the immune system and a plethora of biological mediators. Cell-to-cell communication molecules such as cytokines play an extremely important role in mediating the process of inflammation. Inflammation and platelet activation are critical phenomena in the setting of acute coronary syndromes. An extensive exposition of this complex phenomenon is beyond the scope of this article (Rankin 2004).


Bullous Pemphigoid Soluble Adhesion Molecule Biliary Atresia Patient Human Coronary Artery Endothelial Cell Selectin Ligand 
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44.1 Inflammation

Inflammation is defined as the normal response of living tissue to injury or infection. It is important to emphasize two components of this definition. First, that inflammation is a normal response and, as such, is expected to occur when tissue is damaged. Infact, if injured tissue does not exhibit signs of inflammation this would be considered abnormal and wounds and infections would never heal without inflammation. Secondly, inflammation occurs in living tissue, hence there is need for an adequate blood supply to the tissues in order to exhibit an inflammatory response. The inflammatory response may be triggered by mechanical injury, chemical toxins, and invasion by microorganisms, and hypersensitivity reactions. Three major events occur during the inflammatory response: the blood supply to the affected area is increased substantially, capillary permeability is increased, and leucocytes migrate from the capillary vessels into the surrounding interstitial spaces to the site of inflammation or injury. The inflammatory response represents a complex biological and biochemical process involving cells of the immune system and a plethora of biological mediators. Cell-to-cell communication molecules such as cytokines play an extremely important role in mediating the process of inflammation. Inflammation and platelet activation are critical phenomena in the setting of acute coronary syndromes. An extensive exposition of this complex phenomenon is beyond the scope of this article (Rankin 2004).

Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes (especially granulocytes) from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process. However, chronic inflammation can also lead to a host of diseases, such as hay fever, atherosclerosis, rheumatoid arthritis, and even cancer (e.g., gallbladder carcinoma). It is for that reason that inflammation is normally closely regulated by the body. Acute and chronic inflammation differ in matter of causative agent, major cells involved, primary mediators, onset, duration and final outcomes. Generally speaking, acute inflammation is mediated by granulocytes, while chronic inflammation is mediated by mononuclear cells such as monocytes and lymphocytes.

44.2 Cell Adhesion Molecules

Cell adhesion molecules are glycoproteins expressed on the cell surface and play an important role in inflammatory as well as neoplastic diseases. There are four main groups: the integrin family, the immunoglobulin superfamily, selectins, and cadherins. The integrin family has eight subfamilies, designated as β1 through β8. The immunoglobulin superfamily includes leukocyte function antigen-2 (LFA-2 or CD2), leukocyte function antigen-3 (LFA-3 or CD58), intercellular adhesion molecules (ICAMs), vascular adhesion molecule-1 (VCAM-1), platelet-endothelial cell adhesion molecule-1 (PE-CAM-1), and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). The selectin family includes L-selectin (CD62L), P-selectin (CD62P), and E-selectin (CD62E). Cadherins are major cell-cell adhesion molecules and include epithelial (E), placental (P), and neural (N) subclasses. The binding sites (ligands/receptors) are different for each of these cell adhesion molecules (e.g., ICAM binds to CD11/CD18; VCAM-1 binds to VLA-4). The specific cell adhesion molecules and their ligands that may be involved in pathologic conditions and potential therapeutic strategies by modulating the expression of these molecules have been discussed (Elangbam et al. 1997). Most adhesion molecules play fairly broad roles in the generation of immune responses. The three selectins act in concert with other cell adhesion molecules e.g., intracellular adhesion molecule (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and leukocyte integrins to effect adhesive interactions of leukocytes, platelets, and endothelial cells. The structure and functions of selectins, which belong to C-type lectins family, have been reviewed in  Chaps. 26,  27, and  28.

44.2.1 Selectins

The selectin family of lectins consists of three closely related cell-surface molecules with differential expression by leukocytes (L-selectin), platelets (P-selectin), and vascular endothelium (E- and P-selectin). Structural identity of a selectins resides in its unique domain composition ( Chap. 26). E-, P-, and L-selectin are >60 % identical in their NH2 terminus of 120 amino acids, which represent the lectin domain ( Chaps. 26,  27, and  28). The ligands (counter structures) of selectins are sialylated and fucosylated carbohydrate molecules which, in most cases, decorate mucin-like glycoprotein membrane receptors. Their common structure consists of an N-terminal Ca2+-dependent lectin-type domain, an epidermal growth factor (EGF)-like domain, multiple short consensus repeat (SCR) domains similar to those found in complement regulatory proteins, a transmembrane region, and a short cytoplasmic C-terminal domain. Together this arrangement results in an elongated structure which projects from the cell surface, ideal for initiating interactions with circulating leucocytes. The lectin domain forms the main ligand binding site, interacting with a carbohydrate determinant typified by fucosylated, sialylated, and usually sulphated glycans such as sialyl Lewis X (s-LeX). The EGF domain may also play a role in ligand recognition. The short consensus repeat (SCR) domains (two for L-selectin, six for E-selectin, and nine for P-selectin) probably act as spacer elements, ensuring optimum positioning of the lectin and EGF domains for ligand interaction. The EGF repeats have comparable sequence similarity. Each complement regulatory-like module is 60 amino acids in length and contains six cysteinyl residues capable of disulfide bond formation. This feature distinguishes the selectin modules from those found in complement binding proteins, such as complement receptors 1 and 2, which contain four cysteines ( Chap. 26).

The selectins cell-surface receptors play a key role in the initial adhesive interaction between leukocytes and endothelial cells at sites of inflammation. Selectins (P, E and L) and their ligands (mainly P-selectin ligand) are involved in the rolling and tethering of leukocytes on the vascular wall. Activation of endothelial cells (EC) with different stimuli induces the expression of E- and P-selectins, and other adhesion molecules (ICAM-1, VCAM-1), involved in their interaction with circulating cells. Lymphocytes home to peripheral lymph nodes (PLNs) via high endothelial venules (HEVs) in the subcortex and incrementally larger collecting venules in the medulla. HEVs express ligands for L-selectin, which mediates lymphocyte rolling (Horstman et al. 2004). For structure and functions of selectins, the readers are advised to consult Chaps 26–28. In this chapter we will emphasize mainly on the role of selectins in inflammatory disorders including cancer.

44.3 Atherothrombosis

Atherothrombosis, defined as atherosclerotic plaque disruption with superimposed thrombosis, is the leading cause of mortality in the Western world. Atherosclerosis is a diffuse process that starts early in childhood and progresses asymptomatically through adult life. Later in life, it is clinically manifested as coronary artery disease (CAD), stroke, transient ischaemic attack (TIA), and peripheral arterial disease. From the clinical point of view, we should envision this disease as a single pathologic entity that affects different vascular territories. A suggestive analogy is that TIA and intermittent claudication are the unstable angina of the brain and lower limbs, respectively; and stroke and gangrene are the myocardial infarction. Circulating platelets display reversible interactions with atherosclerotic lesions. Atherosclerotic arterial disease is associated with an increased share of platelets unable to express P-selectin and an increased fraction of platelets that microaggregate in citrate anticoagulant. These platelet alterations are not completely explained by either focal arterial injury or abnormal rheology associated with arterial stenosis but appear to be an effect of the atherosclerotic process (McBane et al. 2004). The pathogenesis of arterial thrombotic disease involves multiple genetic and environmental factors related to atherosclerosis and thrombosis.

44.3.1 Venous Thrombosis

Venous Thrombosis is a world wide health problem in the general population. Injury to the endothelium leads to dysfunction. The causes of injury include lipids, immune complexes, microorganisms, smoking, hypertension, aging, diabetes mellitus and trauma. The selectins are thought to be largely responsible for the initial attachment and rolling of leukocytes on stimulated vascular endothelium. Platelet activation is an important process in the pathogenesis of atherothrombosis. Platelet adhesion, activation, and aggregation at the sites of vascular endothelial disruption caused by atherosclerosis are key events in arterial thrombus formation. Platelet tethering and adhesion to the arterial wall, particularly under high shear forces, are achieved through multiple high-affinity interactions between platelet membrane receptors (integrins) and ligands within the exposed subendothelium, most notably collagen and von Willebrand factor (vWF). Platelet adhesion to collagen occurs both indirectly, via binding of the platelet glycoprotein (GP) Ib-V-IX receptor to circulating vWF, which binds to exposed collagen, and directly, via interaction with platelet receptors GP VI and GP Ia/IIb. Platelet activation, initiated by exposed collagen and locally generated soluble platelet agonists (primarily thrombin, ADP, and thromboxane A2), provides the stimulus for the release of platelet-derived growth factors, adhesion molecules and coagulation factors, activation of adjacent platelets, and conformational changes in the platelet α(IIb)β3 integrin (GP IIb/IIIa receptor). Platelet aggregation, mediated primarily by interaction between the activated platelet GP IIb/IIIa receptor and its ligands, fibrinogen and vWF, results in the formation of a platelet-rich thrombus (Steinhubl and Moliterno 2005).

44.3.2 Arterial Thrombosis

P-selectin expression in platelets is elevated in disorders associated with arterial thrombosis such as coronary artery disease, acute myocardial infarction, stroke, and peripheral artery disease. During thrombosis, P-selectin is expressed on the surface of activated endothelial cells and platelets. P-selectin mediates rolling of platelets and leukocytes on activated endothelial cells as well as interactions of platelets with leukocytes. Platelet P-selectin interacts with PSGL-1 on leukocytes to form platelet-leukocyte aggregates. Furthermore, this interaction of P-selectin with PSGL-1 induces the upregulation of tissue factor, several cytokines in leukocytes and the production of procoagulant microparticles, thereby contributing to a prothrombotic state. P-selectin is also involved in platelet-platelet interactions, i. e. platelet aggregation which is a major factor in arterial thrombosis. P-selectin interacts with platelet sulfatides, thereby stabilizing initial platelet aggregates formed by GPIIb/IIIa-fibrinogen bridges. Inhibtion of the P-selectin-sulfatide interaction leads to a reversal of platelet aggregation. Thus, P-selectin plays a significant role in platelet aggregation and platelet- leukocyte interactions, both important mechanisms in the development of arterial thrombosis. Following activation, P-selectin is rapidly translocated to the cell surface (Merten and Thiagarajan 2004; Wang et al. 2005).

44.3.3 Thrombogenesis in Atrial Fibrillation

Platelet activation occurs in peripheral blood of patients with rheumatic mitral stenosis (MS). The plasma levels of soluble P-selectin are elevated in permanent atrial fibrillation (AF) patients; the plasma levels of soluble P-selectin in the left atrium do not significantly differ from those in the right atrium, femoral vein, or femoral artery. The venous plasma levels of sP-selectin in patients with moderate-to-severe MS are significantly higher than those in healthy volunteers or patients with lone AF. In addition, in patients with MS, there was no difference in the plasma levels of sP-selectin between the left and right atrial blood and between peripheral and atrial blood. Moreover, there was no change in sP-selectin levels as a result of percutaneous transluminal mitral valvuloplasty (PTMV) (Chen et al. 2004). Lip et al. (2005) studied the relations of plasma vWf (an index of endothelial damage and dysfunction) and sP-selectin levels in relation to the presence and onset of clinical congestive heart failure (CHF) and degree of left ventricular dysfunction in patients taking part in SPAF (stroke prevention in AF). While plasma vWf was higher among patients with AF and CHF, plasma P-selectin concentrations were not affected by presence, onset, or severity of heart failure.

44.3.4 Atherosclerosis

Atherosclerosis is a complex chronic inflammatory disease of the arterial wall. Though the inflammatory nature of atherosclerosis has been established, the initial events that trigger this response in the arterial intima remain obscure. Studies reveal a significant rate of genomic alterations in human atheromas. The accumulation of genomic rearrangements in vascular endothelium and smooth muscle cells are important for disease development. It is well accepted that the induction of EC adhesion molecules is a critical component in acute inflammatory responses as well as allogeneic interactions in vascularized allografts and, possibly, atherogenesis. Inflammation and genetics are both prominent mechanisms in the pathogenesis of atherosclerosis and arterial thrombosis. Accordingly, population studies have explored the association of ischaemic heart disease with gene polymorphisms of the inflammatory molecules: tumor necrosis factors (TNF) α and β, transforming growth factors (TGF) β1 and 2, P and E selectins, and platelet endothelial cell adhesion molecule (PECAM) 1. The partly conflicting data provide some evidence that alterations in the genetics of the inflammatory system may modify the risk of ischaemic heart disease. Formation of Reactive Oxygen Species (ROS) as an Initial Event

In recent years, reactive oxygen species (ROS) are considered as initial event in causing atherosclerosis. ROS are a family of molecules including molecular oxygen and its derivatives produced in all aerobic cells. Excessive production of ROS, outstripping endogenous antioxidant defense mechanisms, has been implicated in processes in which they oxidize biological macromolecules, such as DNA, protein, carbohydrates, and lipids. Many ROS possess unpaired electrons and thus are free radicals. These include molecules such as superoxide anion (O 2 ), hydroxyl radical (HO), nitric oxide (NO), and lipid radicals. Other reactive oxygen species, such as hydrogen peroxide (H2O2), peroxynitrite (ONOO), and hypochlorous acid (HOCl), are not free radicals per se but have oxidizing effects that contribute to oxidant stress. The cellular production of one ROS may lead to the production of several others via radical chain reactions. For example, reactions between radicals and polyunsaturated fatty acids within cell membrane may result in a fatty acid peroxyl radical (R-COO) that can attack adjacent fatty acid side chains and initiate production of other lipid radicals. Lipid radicals produced in this chain reaction accumulate in the cell membrane and may have a myriad of effects on cellular function, including leakage of the plasmolemma and dysfunction of membrane-bound receptors. Of note, end products of lipid peroxidation, including unsaturated aldehydes and other metabolites, have cytotoxic and mutagenic properties. A decline in NO bioavailability may be caused by decreased expression of the endothelial cell NO synthase (eNOS), a lack of substrate or cofactors for eNOS (Fig. 44.1 and 44.2).
Fig. 44.1

Mechanisms for oxidant stress-induced endothelial dysfunction in cardiovascular diseases (Hamilton et al. 2004). Excessive production of ROS has been implicated in processes in which they oxidize biological macromolecules, such as DNA, protein, carbohydrates, and lipids. Many ROS possess unpaired electrons and thus are free radicals. These include molecules such as superoxide anion (O 2 ), hydroxyl racial (HO), nitric oxide (NO), and lipid radicals. The cellular production of one ROS may lead to the production of several others via radical chain reactions. A decline in NO bioavailability may be caused by decreased expression of the endothelial cell NO synthase (eNOS), a lack of substrate or cofactors required for eNOS action. Low-density lipoprotein (LDL) is oxidized to oxidized form of LDL (ox-LDL) and initiates the atherosclerotic process in the vessel wall (see Fig. 44.2). Abbreviations: O2−, superoxide; NO, nitric oxide; ONOO−, peroxynitrite; H2O2, hydrogen peroxide; OH−, hydroxyl radical; SOD, superoxide dismutase; GSH, reduced glutathione; GSSG, oxidised glutathione; VSM, vascular smooth muscle

Fig. 44.2

Oxidation of LDL initiates the atherosclerotic process in the vessel wall by acting as a potent stimulus for the induction of inflammatory gene products in vascular endothelial cells. By activating the NF-kB transcription factor, oxidized LDL (ox-LDL) stimulates increased expression of cellular adhesion molecules. There are several different types of adhesion molecules with specific functions in the endothelial leukocyte interaction: The selectins tether and trap monocytes and other leukocytes. Importantly, VCAMs and ICAMs mediate firm attachment of these leukocytes to the endothelial layer. Ox-LDL also augments expression of monocyte chemoattractant protein 1 (MCP-1) and macrophage colony stimulating factor (M-CSF). MCP-1 mediates the attraction of monocytes and leukocytes and their diapedesis through the endothelium into the intima. M-CSF plays an important role in the transformation of monocytes to macrophage foam cells. Macrophages express scavenger receptors, which internalize oxLDL in their transformation into foam cells. Migration of smooth muscle cells (SMCs) from the intima into the media is another early event initiating a sequence that leads to formation of a fibrous atheroma

In mammalian cells, potential enzymatic sources of ROS include the mitochondrial respiration, arachidonic acid pathway enzymes lipoxygenase and cyclooxygenase, cytochrome p450s, xanthine oxidase, NADH/NADPH oxidases, NO synthase, peroxidases, and other hemoproteins. Although many of these sources could potentially produce ROS that inactivate NO, 3 sources have been studied extensively in cardiovascular system. These include xanthine oxidase, NADH/NADPH oxidase, and NO synthase (Cai and Harrison 2000; Hamilton et al. 2004; Vijya Lakshmi et al. 2009). CAMs as Predicators of Atherosclerosis

During initial step in atherosclerosis, there is rapid targeting of monocytes to the sites of inflammation and endothelial injury; the adhesion of leukocytes to activated endothelial cells is mediated by ICAM-1. The induction of EC adhesion molecules is a critical component in acute inflammatory responses as well as allogeneic interactions in vascularized allografts and, possibly, atherogenesis. The "inflammatory triad" of IL-1, TNF, and LPS are potent stimulators of the EC activation and adhesion molecules E-selectin or ELAM-1 (or also known as CD62E), ICAM-1 and VCAM-1. PECAM-1 plays also a key role in the transendothelial migration of circulating leukocytes (diapedesis) during vascular inflammation. ICAM-1 and VCAM-1 are inflammatory predicators of adverse prognosis in patients with acute coronary syndromes (ACS) (Postadzhiyan et al. 2008) (Fig. 44.2).

Levels of P-selectin are increased in the blood of patients with familial hypercholesterolemia (FH) in spite of long-term intensive extracorporeal LDL-elimination, documenting the activity of atherosclerosis. Low levels of P-selectin and MCP-1 after hypolidemic procedure can be used as a marker showing the effectivity of the extracorporeal LDL-cholesterol elimination (Blaha et al. 2004). In an extended study, the levels of expression of tissue factor, ICAM-1, P- and E-selectin, and PAI-1 were found low, whereas those of endothelial protein C receptor and VCAM-1 were high (Merlini et al. 2004). Gene Polymorphisms in E-Selectin

Polymorphisms in the E-selectin gene are associated with accelerated atherosclerosis in young (age <40 years) patients, further suggesting a role of inflammation in atherosclerosis. A further change in endothelial physiology is an increase in the surface expression of E-selectin, which regulate adhesive interactions between certain blood cells and endothelium. Intravascular fibrinolysis induced by tissue-type plasminogen activator or urokinase may contribute to the initiation of atherosclerosis by inducing P-selectin and platelet activating factor as well as to plaque rupture, either directly or indirectly, by activating metalloproteinases. As E-selectin is only expressed on activated endothelium, it provides an opportunity to study pathophysiological aspects of this cell in cardiovascular and other disease. However, sE-selectin can be found in the plasma, which has potential role in the pathogenesis of cardiovascular disease as raised levels have been found in hypertension, diabetes and hyperlipidemia, although its association in established atherosclerosis disease and its value as a prognostic factor is more controversial (Holvoet and Collen 1997).

Polymorphisms for three genes, P-selectin, L-selectin, and E-selectin (genes P-sel, L-sel, and E-sel, respectively) showed that the selectin cluster is linked to markers at chromosome 1q23 (Vora et al. 1994). Significant genomic alterations were found on 1q22-q25 in Sel-L gene. The message indicated somatic DNA rearrangements, on loci associated to leukocyte adhesion, vascular smooth muscle cells growth, differentiation and migration, to atherosclerosis development as an inflammatory condition (Arvanitis et al. 2005). Wenzel et al. (1999) and Yoshida et al. (2003) described an adenine to cytosine (A/C) substitution for cDNA position 561 resulting in an amino acid exchange from serine to arginine at position 128 (S/R or Ser128Arg) was detected in the epidermal growth factor (EGF) domain. A higher mutation frequency was observed in patients aged 50 years or less with proven severe atherosclerosis as well as in patients aged 40 years or less. If Ser128Arg substitution had an effect on the adhesion of blood cells to the endothelium, the polymorphism could be of interest with respect to association studies in a number of pathological conditions, such as cardiovascular diseases. The Ser128Arg polymorphism is associated with a higher risk for early severe atherosclerosis. Yoshida et al. (2003) suggested that the E-selectin Ser128Arg polymorphism could functionally alter leukocyte-endothelial interactions as well as biochemical and biological consequences, which may account for the pathogenesis of myocardial infarction (Li et al. 2005). Leu554Phe E-selectin mutations in Hypertension and CAD

Wenzel et al. (1996, 1999) detected 17 mutations, five of which resulted in an amino acid substitution. In E-selectin, exchange at Ser128Arg in EGF domain and Leu554Phe in membrane domain, and a DNA mutation from guanine to thymine (position 98) presented different allele frequencies in young patients with severe atherosclerosis, compared with an unselected population. The bi-allelic A/C polymorphism in the E-selectin gene may be implicated in the clinical expression of erythema nodosum (EN) secondary to sarcoidosis (Amoli et al. 2004). However, the E-selectin polymorphism may be associated with severity of atherosclerotic disease, but it is unknown if it is actually a risk factor for atherosclerosis (Ghilardi et al. 2004). A strong relationship was confirmed between 561A > C and 98G > T polymorphisms of E-selectin gene and susceptibility to CAD by Zak et al. (2008). A body mass index (BMI)-specific effect of Leu554Phe polymorphism of E-selectin gene on blood pressure has been reported by Marteau et al. (2004) who strengthened the view that E-selectin is implicated in hypertension (Marteau et al. 2004). Serum levels of E- and P-selectin in patients with essential hypertension (EH) are significantly higher than in controls, where as differences in serum levels of soluble L-selectin, VCAM-1, or ICAM-1 between the patients with EH and the controls were not different (Sanada et al. 2005). Genomic Arrangement of P-Selectin Gene P-Selectin Thr715Pro (A/C) Polymorphism

Genetic analyses of P-selectin in the progression of atherosclerosis have provided conflicting results regarding the role of variation within the P-selectin gene and risk for heart disease. Miller et al. (2004b) suggested that the Thr715Pro C allele was rare in blacks (0.8 %) and intermediate in South Asians (3.0 %) compared to whites (11.2 %). sP-selectin levels were significantly lower in the individuals with the AC or CC compared to the AA genotype in both whites and South Asians. Thus, in whites and South Asians the C allele of the Thr715Pro P-selectin polymorphism is associated with lower sP-selectin levels (Miller et al. 2004b). The P-selectin Thr715Pro polymorphism is not associated with incident CHD or ischemic stroke in either whites or African-Americans (Volcik et al. 2006). Predictive Value of sE-Selectin in CAD

In CAD, inflammatory biomarkers have been extensively investigated; more evidence exists for C-reactive protein (CRP;  Chap. 8). Fatty acid (FA) composition in serum has been associated with CRP and E-selectin but not with other inflammatory markers (Petersson et al. 2009). Studies suggest that, besides CRP, other inflammatory biomarkers such as cytokines, s-CD40 ligand, serum amyloid A (SAA), selectins (E-selectin, P-selectin), ICAM-1, VCAM-1, and several others may have a potential role for the prediction of risk for developing CAD and may correlate with severity of CAD (Eikemo et al. 2004; Fang et al. 2004; Potapov et al. 2005; Zakynthinos and Pappa 2009). The combination of natriuretic peptide (BNP) and E-selectin offers increased predictive value. Plasma levels of adhesive molecules are correlated in patients with stable IHD. Cigarette smoke condensate (CSC)-induced surface expression of ICAM-1, E-selectin, and VCAM-1 in HUVEC. Fang et al. (2005) reported a significant decrease in C allele frequency of PECAM-1 gene and showed that Leu125Val polymorphism of PECAM-1 gene and elevated soluble PECAM-1 were related to severe coronary artery stenosis in CAD patients.

44.3.5 Myocardial Infarction

sP-Selectin is Associated with Myocardial Damage: Platelets are known to be activated during myocardial infarction (MI). Though, the levels of sP-selectin, sE-selectin and sPECAM-1 did not differ significantly in the pathogenesis of atherosclerosis, sP-selectin was substantially increased in patients with acute myocardial infarction (AMI). Yip et al. (2006) tested the hypothesis that platelet activity shown by CD62P is enhanced and predictive of both the extent of myocardial damage and 30-day clinical outcome in patients with ST-se AMI undergoing primary coronary stenting. Xu et al. (2006) suggested that activated-platelets play an important role in the process of myocardial ischemia-reperfusion injury, and platelet-derived P-selectin is a critical mediator. P-selectin expression, along with CD40 ligand and tissue factor is significantly increased in infarcted rabbits with respect to controls. Clopidogrel administration reduced P-selectin expression and CD40 ligand (Molero et al. 2005).

Hyperhomocysteinemia and Selecins in MI: Hyperhomocysteinemia is regarded as an independent risk factor for vascular diseases, and homocysteine is supposed to contribute to oxidative stress and endothelial damage. Hyperhomocysteinemia is significantly associated with MI in comparison with controls with an odd ratio of 6.26 (Khare et al. 2005). Folic acid corrected and reduced hyperhomocysteinemia in a large majority of the cases. Although the levels of sP-selectin, sE-selectin and sPECAM-1 decrease after folic acid therapy, it was only sE-selectin which was significantly reduced. Apart from their lipid-lowering capacity, statins also exert anti-inflammatory and antioxidant effects.

DNA Polymorphism in MI: Some polymorphisms may increase the risk of MI within specific ethnic groups or in certain populations. P-selectin expression is increased in atherosclerotic plaques, and high plasma levels of this molecule have been observed in patients with unstable angina. DNA polymorphisms in P-selectin gene may be a possible candidate for MI. The P-selectin gene is situated on chromosome 1q21-q24, spans >50 kb and contains 17 exons. Four polymorphisms (Ser290Asn, Asn562Asp, Leu599Val and Thr715Pro) predicted a change in the amino acid sequence of P-selectin. In patients with MI from four regions of France and Northern Ireland (the ECTIM study) the P-selectin polymorphisms provided a heterozygosity of 91 %. The polymorphisms were tightly associated with one another and displayed patterns of linkage disequilibrium suggesting the existence of highly conserved ancestral haplotypes. Study illustrates the complexity of the relationship between gene variability and disease and the necessity to explore in detail the polymorphisms of candidate genes (Herrmann et al. 1998; Tregouet et al. 2002).

The E-selectin gene Arg128, 98 T, and Phe554 alleles and PECAM1 Leu125Val and Ser563Asn polymorphisms may increase the risk of atherosclerosis, but not necessarily the risk of MI. This association seems to be more pronounced in younger patients and may be especially important in patients with a low risk for developing atherosclerosis. Reports indicated that screening for CD14-260 C/T genotypes is unlikely to be a useful tool for risk assessment and it remains unclear whether CD14 polymorphisms significantly increase the risk of MI. The A252G polymorphism of lymphotoxin-α (LTA) gene, a member of the TNF family, is strongly related with the onset of AMI (Auer et al. 2003). Quantitative real-time RT-PCR confirmed that LTA increased the expressions of E-Selectin and VCAM1 both in HUVEC and HCAEC, suggesting the roles of LTA in the development of atherosclerosis. Aminian et al. (2007) determined the possible role of Gly241Arg and Lys469Glu polymorphisms in development of CAD and acute or chronic MI. Although the frequency of Gly-Arg and Arg-Arg genotypes were higher in the control group compared to the CHD patients, no strong corelation was found between Gly241Arg and Lys469Glu polymorphisms and occurrence of CHD and MI in population from Iran.

44.3.6 Atherosclerotic Ischemic Stroke

In ischemic event in patients with atherosclerotic ischemic stroke, though the platelet aggregability was decreased after day 3 compared to that at day 1 of stroke onset, platelet CD63 and P-selectin/CD62P expression remained high even 90 days after the events. This suggested that platelet hyperactivation in atherosclerotic ischemic stroke might be sustained for a considerable period (Cha et al. 2004; Nadar et al. 2004b; Yip et al. 2006). Blood levels of ICAM-1 and CD62P expression in different typing of patients with ischemic stroke are different. Evidences suggest that MPS (Meridian-phlegm stagnancy) group of patients is the key pathogenic factor of ischemic stroke.

Mucosal tolerance to E-selectin after booster tolerization can relieve cerebral ischemia-reperfusion injury and induce ischemia tolerance in rats. The mechanisms may involve decreased frequencies of CD8+ T cells, heightened mRNA expression of IL-10 and lowered mRNA expression of E-selectin in the ischemic hemisphere (Yun et al. 2008). Selakovic et al. (2009) defined changes of soluble CAMS in cerebrospinal fluid and plasma in the patients with the acute brain infarction, in which significant increase in the level of soluble adhesion molecules occurs within the first seven days. Studies show that hypoxia/reoxygenation stimulates ICAM-1 and apoptosis (Antonova et al. 2009).

Cerebral arteriovenous malformations (AVMs) showed significant upregulation of E-selectin, VCAM-1 and ICAM-1 (Storer et al. 2008; Chan and Sukhatme 2008; Tuttolomondo et al. 2009). Li et al. (2008) showed that ICAM-1 Lys469Glu polymorphism was involved in the causation of ischemic stroke, especially in female but not in male (Rodrigues et al. 2008). Two allelic variants were related to ischemic stroke. Multivariable regression analysis after adjustment for vascular risk factors demonstrated that alleles Arg of Ser128Arg and Phe of Leu554Phe polymorphisms are independent risk factors for ischemic stroke. The combination of two minor alleles of E-selectin genes appeared to be the strongest susceptibility factor for ischemic stroke (Haidari et al. 2009). Sarecka-Hujar et al. (2010) could not confirm the relationship between the 98 G > T polymorphism of the E-selectin gene and childhood ischemic stroke. The G allele of the E- selectin 98 G > T polymorphism was more frequently transmitted to the children after stroke compared to the T allele. There is a need for further studies in these areas.

44.3.7 Hypertension

The association between blood pressure and different adhesion molecules appeared to be present in women younger than 50 years, who were likely to be pre-menopausal (Miller et al. 2004a). Serum levels of E- and P-selectin in patients with essential hypertension (EH) are significantly higher than in the controls (Sanada et al. 2005). After adjustment for age, only sE-selectin concentrations were significantly associated with blood pressure. Higher levels of plasma sP-selectin were confirmed in hypertensive patients alone with VEGF (Nadar et al. 2004a). It is stated that decrease in blood pressure may reduce the rate of progression of atherosclerosis by affecting the expression of E- and P-selectin in the endothelium, the platelets, or both.

44.3.8 Reperfusion Injury

In vitro studies indicate that complement activation regulates the expression of P-selectin on endothelial cells. This suggests that in disorders such as ischemia/reperfusion injury, in which both complement and P-selectin have been shown to play a role, complement activation is a primary event and the effects of P-selectin are secondary. In mouse kidney model of I/R injury, results indicated that complement and P-selectin-mediated pathways of renal reperfusion injury are mutually independent (Farrar et al. 2004). Induction of circulating polymorphonuclear neutrophils (PMNs) might contribute to the superior outcome following stenting and early intervention compared to conventional balloon angioplasty (PTCA). A substantial increase in sE-selectin levels early after PTCA and stent implantation may predict development of restenosis (Heider et al. 2006; Kilickap et al. 2004). After reperfusion of myocardial vessels, P-selectin expressed on majority of vessels (77 %) though the expression decreased during subsequent remaining duration of reperfusion (Chukwuemeka et al. 2005). In rats, the mRNA expression for several genes was associated with inflammation after transient middle cerebral artery occlusion (MCAO). Gene expression increased in the injured hemisphere for IL-1β, IL-6 and ICAM-1. TNF-α mRNA was upregulated in the injured versus uninjured hemisphere, while E-selectin mRNA showed a significant increase from 6 to 24 h after MCAO (Berti et al. 2002). Both P-selectin and LFA-1 may be important targets to control pathologic inflammation in I/R-induced tissue injury in the colon (Riaz et al. 2002). The study in intestinal ischemia and reperfusion injury (IR/I) using murine models demonstrated the importance of P-selectin in warm and cold IR/I. The blockade of P-selectin using rPSGL1-lg or the absence of P-selectin KO mice confers a survival advantage and reduction in tissue injury. The mechanism appears to be independent of neutrophil infiltration (Carmody et al. 2004). Enterocyte apoptosis is increased following intestinal I/R injury. Hyperoxia following intestinal I/R in rat increased E-selectin expression in the jejunum and ileum and a concomitant increase in neutrophil recruitment in the ileum, accompanied by increased cell apoptosis (Braun et al. 2004; Sukhotnik et al. 2008). Germ cell-specific apoptosis that occurs after I/R of murine testis is dependent on neutrophil recruitment to the testis and is dependent on E-selectin. Blockage of E-selectin may be a strategy to treat post-ischaemic testis (Celebi and Paul 2008).

44.4 CAMS in Allergic Inflammation

Allergic inflammation is characterized by recruitment of specific leukocyte subpopulations from blood into tissue and requires a series of cell adhesion-molecule-mediated interactions between postcapillary vascular endothelium and the leukocyte cell surface. Three major groups are involved: selectins, integrins, and the immunoglobulin gene superfamily. P- and E-selectin mediate initial leukocyte adhesion, whereas beta 2-integrin/ICAM-1 and VLA-4/VCAM-1 pathways mediate leukocyte arrest and transendothelial migration. Because VLA-4 expression is restricted to eosinophils and lymphocytes, VCAM-1 has been implicated in selective eosinophil recruitment characterizing allergic inflammation. However, additional factors such as profile of cytokine release are likely to operate since tissue eosinophilia has been observed in the absence of VCAM-1 expression (Smith et al. 1993a).

44.4.1 Dermal Disorders

E-selectin is highly expressed on vascular endothelium in atopic dermatitis and psoriasis, and in patients with measles. The cutaneous lymphocyte-associated antigen (CLA), which is expressed on peripheral skin-homing helper memory T cells in healthy persons, is at least partly the sialyl 6-sulfo Lex determinant (Ohmori et al. 2006) and a ligand for selectins. The differential polyadenylation of E-selectin transcripts may provide the molecular basis for the observed chronic expression of E-selectin in human dermal disorders. In atopic dermatitis, patients express ICAM-1 and ICAM-3, E-selectin and L-selectin (60 %) in the dermis, without expression of E- and L-selectins in the epidermis. A high expression of adhesion molecules in the skin lesions of atopic dermatitis patients may play an important role in the pathogenesis of atopic dermatitis (Lugovic et al. 2006). The blood markers for atopic dermatitis, including soluble forms of E-selectin, VCAM-1 and ICAM-1 were reduced after treatment with cetiridine (Izu and Tokura 2005). The extracts from dust mites, Dermatophagoides farinae, D. pteronyssinus and Euroglyphus maynei with and without endotoxin (LPS) stimulated endothelial cells to express ICAM-1, VCAM-1, and E-selectin and to secrete IL-6, IL-8, MCP-1, and GM-CSF. Serum levels of sE-selectin are higher in children with measles than in children with atopic dermatitis, atopic asthma and healthy controls. But it was not correlated with measles. There was no correlation between sE-selectin and TNF-α level (Park et al. 2008). Pollinosis from Parietaria judaica is one of the main causes of allergy in the Mediterranean area. The treatment of endothelial cells with pollen extract causes an increase of E-selectin and VCAM-1 protein levels as well as an increase of IL-8 production. The stimulation of cell adhesion molecules was paralleled by an increase of adhesion of polymorphonuclear cells (PMNs) to HMVEC-L monolayer (Taverna et al. 2008).

44.4.2 Rhinitis and Nasal Polyposis

Allergic rhinitis is an inflammatory disease of the nasal mucosa, caused by an IgE-mediated reaction after exposure to the allergen. Persistent inflammation is induced by the presence of an inflammatory cell infiltrate, together with ICAM-1 expression in the epithelial cells of the mucosa exposed to the allergen to which they are sensitized, in the absence of clinical symptoms (Montoro et al. 2007). Nasal polyposis is a chronic non-infectious inflammatory disease of the nasal and paranasal cavity mucosa. Eosinophil migration from blood stream to nasal polyps involves different molecules such as ICAM-1, VCAM-1, and L-, P- and E-selectins. Patients with nasal polyposis exhibit a higher expression of VCAM-1, E-selectin, and L-selectin compared to healthy controls (Corsi et al. 2008). Staphylococcal enterotoxin A (SEA) and staphylococcal enterotoxin B (SEB) infection increased ICAM-1 expression and cytokine secretion (Wang et al. 2007).

44.4.3 Lung Injury

Excessive leukocyte accumulation is involved in the pathogenesis of the sepsis-induced acute lung injury. Studies suggest that P-selectin has a substantial role in the pathogenesis of the lung injury induced by LPS (Ohnishi et al. 1999). In bleomycin-induced fibrosis in mice, the L-selectin and/or ICAM-1 deficiency inhibited skin and lung fibrosis with decreased Th2 and Th17 cytokines and increased Th1 cytokines. In contrast, P-selectin deficiency, E-selectin deficiency with or without P-selectin blockade, or PSGL-1 deficiency augmented the fibrosis in parallel with increased Th2 and Th17 cytokines and decreased Th1 cytokines. Yoshizaki et al. (2010) suggest that L-selectin and ICAM-1 regulate Th2 and Th17 cell accumulation in skin and the lung, leading to the development of fibrosis, and that P-selectin, E-selectin, and PSGL-1 regulate Th1 cell infiltration, resulting in the inhibition of fibrosis (Yoshizaki et al. 2010). Adult respiratory distress syndrome (ARDS) appears to develop as the acute lung injury in the course of many severe diseases, as the result of damage of alveolar-capillary barrier. Clinical observations suggest that analysis of E-, P-selectin and ICAM-1 concentrations in the serum of patients with ARDS may be helpful in monitoring the course and treatment of the disease (Skiba-Choińska and Rogowski 1996). In the pathogenesis of paracoccidioidomycosis, Gonzalez et al. (2005) suggest that during early stages, up-regulation of ICAM-1, VCAM-1, CD18 and Mac-1 expression may participate in the inflammatory process.

44.4.4 Bronchial Asthma and Human Rhinovirus

The house dust mite (HDM) is the common indoor allergen associated with bronchial asthma. ICAM-1, VCAM-1, and E-selectin are newly synthesized prior to spontaneous asthma attacks, and their expression may play a key role in eosinophil infiltration into the airway (Ohkawara et al. 1995). Crude extract of D. farinae induces ICAM-1 expression in EoL-1 cells through signaling pathways involving both NF-kB and JNK (Kwon et al. 2007). Kirchberger et al. (2006) demonstrated that signaling via ICAM-1 induces adhesiveness of mononuclear phagocytes, which critically involves PECAM-1 and is mediated via LFA-1/ICAM-3. The most common acute infection in humans, Human Rhinovirus (HRV) is a leading cause of exacerbations of asthma and chronic obstruction pulmonary disease. ICAM-1 is a critical target-docking molecule on epithelial cells for 90 % HRV serotypes. ICAM-1 regulates not only viral entry and replication but also signaling pathways that lead to inflammatory mediator production (Lau et al. 2008; Lee et al. 2008). The sICAM-1 but not sE-selectin from patients with asthma is significantly higher than healthy controls. Although serum levels of sICAM-1 are higher in asthmatics, it may be necessary to establish individual baseline values for serial estimation to evaluate their clinical relevance (Bijanzadeh et al. 2009). The serum levels of sICAM-1 were significantly higher in obese nonasthmatic and obese asthmatic children versus control and lean asthmatic children (Huang et al. 2008). P-selectin is an important controller of the inflammation by mediating selective eosinophil cell influx to the lung. It can be used as a sensitive marker in mild asthma (Sjosward et al. 2004).

44.5 Autoimmune Diseases

Adhesion molecule expression and interactions are involved in initiation and propagation of autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus, Sjögren's syndrome, autoimmune thyroid disease, multiple sclerosis, systemic sclerosis (SSc) and diabetes mellitus. Increased adhesion molecule expression and avidity changes occurring with cellular activation are the principal methods regulating leukocyte adhesion. Although differences between specific autoimmune diseases exist, key interactions facilitating the development of autoimmune inflammation appear to include L-selectin/P-selectin/E-selectin, LFA-1/ICAM-1, very late antigen-4 (VLA-4)/VCAM-1, and α4B7/MadCAM or VCAM-1 adhesion. A vast array of adhesive interactions occurs between immunocompetent cells, endothelium, extracellular matrix, and target tissues during the evolution of an autoimmune disease. Dermatitis herpetiformis (DH) and bullous pemphigoid (BP), the autoimmune diseases, are characterized by destruction of the basement membrane zone (BMZ) and anchoring fibres by autoantibodies and infiltration. Skin biopsies from patients with DH, with BP, and from healthy subjects showed the expression of E and L selectins mainly in the skin leukocytes in all samples where as β1, β3 integrins was detected mainly in basal keratinocytes. Integrins and selectins seem to play an important role in the destruction of BMZ in DH and BP (Erkiert-Polguj et al. 2009). P-selectin levels were significantly higher than normal in RA and SSc, but not in SLE. In contrast, mean L-selectin levels were significantly higher than normal in SLE, but not in RA or SSc. Where as soluble IL-2 receptors in patients with active RA, SSc and SLE were almost double the normal level, showing a strong positive correlation only between L-selectin and sIL-2R, and only in patients with SLE. These findings indicated a distinct pattern of immune cell activation in chronic diseases that share an over-activation of T-lymphocytes (Sfikakis and Mavrikakis 1999).

44.5.1 Endothelial Dysfunction in Diabetes (Type 1 Diabetes)

Adhesion molecules have been implicated in the development and progression of cardiovascular disease, particularly in people with diabetes. Diabetes mellitus type 1 (Type 1 diabetes or T1DM, also called insulin-dependent diabetes mellitus—IDDM, or, formerly, juvenile diabetes) is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing β cells of the pancreas. The chronic hyperglycemic state in T1DM patients produces an aggression to vascular endothelium leading to a premature development of atherosclerosis. In both boys and girls, sE-selectin is an early marker of endothelial dysfunction and a probable risk marker of atherosclerosis in children with T1DM (Carrizo et al. 2008). The levels of C-reactive protein, E-selectin, and cytokines in association with severity index were significantly increased in T1DM and type 1 diabetic patients with microvascular complications (T1DM-MV patients) compared with control subjects (Devaraj et al. 2007). Nerve microvasculitis and ischemic injury appear to be the primary and important pathogenic alterations in lumbosacral radiculoplexus neuropathy (LRPN) of patients with diabetes mellitus (DLRPN) and without diabetes mellitus (LRPN). The up-regulation of inflammatory mediators target different cells at different disease stages and that these mediators may be sequentially involved in an immune-mediated inflammatory process that is shared by both DLRPN and LRPN (Kawamura et al. 2008).

Adhesion molecules are upregulated in endothelial cells of the placental bed in pregnancies complicated by T1DM in association with increased adherence of peripheral blood monocytes. The increase in monocyte adhesion to decidual endothelial cells from diabetic pregnancies was associated with increased endothelial cell expression of ICAM-1, but not VCAM-1. ICAM-1 expression in normal decidual endothelial cells was stimulated by pro-atherogenic and pro-inflammatory stimuli (Xie et al. 2008; Telejko et al. 2009).

Type 2 Diabetes: In contrast to T1DM, type 2 diabetes mellitus (T2DM) results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency (Formerly referred to as non-insulin-dependent diabetes mellitus, NIDDM for short). Endothelial dysfunction in type 2 diabetic patients is associated with inflammation, increased levels of circulating soluble adhesion molecules (VCAM-1 and E-selectin), and inducing production of ROS, and urinary albumin excretion (Potenza et al. 2009). Diabetic patients have increased susceptibility to infection, which may be related to impaired inflammatory response observed in experimental models of diabetes, and restored by insulin treatment (Riad et al. 2008; West et al. 2008).

Serum Levels of CAMs in Diabetic Patients: Abnormal levels some of serum ICAM-1, VICAM-1, E-selectin, P-selectin, L-selectin have been detected in T2DM. High-fat load and glucose alone produce an increase of nitrotyrosine, ICAM-1, VCAM-1, and E-selectin plasma levels in normal and diabetic subjects. A decrease in neutrophil surface CD62L expression and significantly higher concentrations of sICAM-1, sVCAM-1, sE-selectin, vWF, hsCRP, IL-6 and fibrinogen in patients with diabetic microangiopathy in comparison with diabetic group without microangiopathic complications and healthy controls suggested that: (1) diabetic microangiopathy is accompanied by increase in CD11b expression and decrease in CD62L (L-selectin) expression on peripheral blood neutrophils; (2) neutrophil activation and intensified adhesion; (3) the development of diabetic microangiopathy is accompanied by an increase in soluble adhesion molecules and inflammatory markers concentrations in the blood (Lim et al. 2004; Mastej and Adamiec; 2008). Levels of E-selectin positively correlated with high triglyceride levels in type 2 diabetic subjects with silent ischemia (Adamikova et al. 2008; Okapcova and Gabor 2004; Rubio-Guerra et al. 2008). Though, baseline plasma levels of vascular markers (hsCRP, sICAM-1, sVCAM-1, E-selectin and P-selectin) were significantly elevated, they did not improve after aerobic exercise. The sE-selectin and vWF are elevated in chronic heart failure patients with DM but not in those without DM. High sE-selectin levels may be associated with ischaemic events in patients with DM (Kistorp et al. 2008).

Diabetic Nephropathy (DN) and Diabetic Heart: Diabetic nephropathy (DN) is the leading cause of end stage renal disease (ESRD) (Malatino et al. 2007). Although the pathogenesis of DN is multifactorial, local inflammatory stress may result from both the metabolic and hemodynamic derangements observed in DN. The current evidence supporting the role of inflammation in the early phases of clinical and experimental DN has been reviewed (Fornoni et al. 2008). Inflammatory markers such as IL-18 and TNF-α are increased in the serum of patients with diabetes and DN. This occurs at an early stage of disease, and correlates with the degree of albuminuria. The pharmacologic interventions for DN by angiotensin converting enzyme inhibitors, angiotensin receptor blockers and aldosterone antagonists may have anti-inflammatory effects, which are independent of their hemodynamic effect.

Diabetic Retinopathy: The association between soluble adhesion molecules levels and retinopathy in type 2 diabetic patients has been clarified. sE-selectin levels are elevated in diabetic patients compared to control subjects, with no significant difference in sICAM-1 and sVCAM-1 levels. The progression of retinopathy was not associated with an increase in soluble adhesion molecules. However, Nowak et al. (2008) observed that serum levels of sICAM-1 and sELAM-1 were significantly elevated and the concentration sVCAM-1 was elevated but not significantly in diabetic patients. Increase in sICAM-1 and sVCAM-1 levels, as well as their correlation with high vitreous IL-6 and TNF- α concentrations in patients with diabetic retinopathy seems to confirm the inflammatory-immune nature of this process. Significantly increased TNF-α concentration in the vitreous body was related to the rise of VCAM-1 (Adamiec-Mroczek and Oficjalska-Młyńczak 2008; Leal et al. 2008; Khalfaoui et al. 2008). Intravitreal injection of corticosteroid has been used to treat diabetic macular edema.

44.5.2 Rheumatic Diseases

Plasma levels of vWF and sP-selectin (but not sE-selectin) are significantly higher among Rheumatoid disease (RD) patients compared to controls. Levels of vWF progressively rise with increasing cardiovascular risk (Bhatia et al. 2009). Serum levels of ICAM-1, ICAM-3, VCAM-1, L-selectin, and E-selectin have been detemined in children with a variety of pediatric rheumatic diseases. A trend toward higher levels of sE-selectin was found in vasculitis vs other diagnoses. The sICAM-1 was higher in patients with active vs inactive disease across all diagnoses. Report suggests that (1) elevated E-selectin levels in vasculitis likely reflect the high degree of endothelial activation and possibly overt vascular damage in those conditions. (2) The correlation of sL-selectin with C4 in SLE may indicate that downregulation of shedding of cell surface L-selectin is involved in continued adherence of leukocytes to endothelium, possibly causing further damage and immune complex deposition in this condition. (3) The trend toward inverse correlation between sE-selectin and vWF:Ag in diabetes mellitus is interesting. (4) Levels of sICAM- I may be a useful marker of active vs quiescent disease in general in the pediatric rheumatic diseases, although lack of correlation with disease activity indices indicates that it is too insensitive to smaller differences in disease activity to be recommended for routine clinical use (Bloom et al. 2002).

44.5.3 Rheumatoid Arthritis

Considerable evidence indicates that patients with Rheumatoid arthritis (RA) are at greater risk of developing atherosclerosis and cardiovascular disease. Atherosclerotic cardiovascular mortality is increased in RA patients. The markers proposed for assessing RA activity include rheumatoid factor, anti-citrullinated protein/peptide antibodies, IgM anti-IgG advanced glycation end products, markers of bone/cartilage metabolism, mannose-binding lectin, E-selectin, IL-6, and leptin. Various studies have investigated the correlation between some of these markers and other variables that might indicate disease activity, e.g., inflammatory activity tests and disease activity scores. However, there is as yet insufficient evidence that any of these markers, in isolation or in combination, are useful in the assessment of RA activity. Many numerous endothelial cells become positive for E-selectin and E-selectin mRNA in RA synovial membranes and the E-selectin expression appeared to correlate with inflammatory activity. P-selectin deficiency in mice resulted in accelerated onset of joint inflammation in the murine collagen-immunized arthritis model. Mice deficient either in E-selectin or in E- selectin and P-selectin (E/P-selectin mutant) also exhibit accelerated development of arthritis compared with wild type mice in CIA model. The strong vascular expression of E-selectin indicates an activation of endothelial cells in the recruitment of cells associated with the chronic inflammation of RA (Foster et al. 2009; da Mota et al. 2009). E-Selectin and ICAM-1 are upregulated on the synovial endothelium, while VCAM-1 plays an important role in synovial lining layer cells and within the synovial stroma. The expression of CAMs may be blocked by mAbs and modified by nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs. (Cobankara et al. 2004). Serum soluble adhesion molecules concentrations are down-regulated following anti-TNF-α antibody therapy combined with methotrexate (MTX) (Klimiuk et al. 2004, 2007; Levälampi et al. 2007; Bosello et al. 2008).

In comparison with osteoarthritis (OA), patients with early RA are characterized by high serum concentrations of sICAM-1, sVCAM-1, and sE-selectin (Yildirim et al. 2005), while LDL-cholesterol was decreased in all RA patients (Pemberton et al. 2009). P-selectin deficiency in mice results in accelerated onset of joint inflammation in the murine collagen-immunized arthritis model. Mice deficient either in E-selectin or in E-selectin and P-selectin (E/P-selectin mutant) also exhibit accelerated development of arthritis compared with wild type mice, suggesting that these adhesion molecules perform overlapping functions in regulating joint disease. Ruth et al. (2005) suggested that E-selectin and P-selectin expression can significantly influence cytokine and chemokine production in joint tissue, and that these adhesion molecules play important regulatory roles in the development of RA in E/P-selectin mutant mice (Singh et al. 2008).

In RA patients, P-selectin expression, PMC and sCD40L levels were increased when compared with controls. The increase in markers of active platelets, P-selectin and sCD40L, and platelet-monocyte levels might be associated with the increased cardiovascular mortality in RA. Psoriatic arthritis (PsA) is associated with the development of endothelial dysfunction and increased atherosclerotic complications. Endothelial activation might have a role in the pathogenesis of both psoriasis and PsA. Among parameters of platelet activation, only PMC might play a role in the pathogenesis of PsA (Pamuk et al. 2008, 2009). Though, sE-selectin correlated with severity of joint disease, further follow-up studies should evaluate if sE-selectin is useful as prognosis marker for progression of articular damage (Corona-Sanchez et al. 2009).

44.5.4 Other Autoimmune Disorders

Systemic Lupus Erythematosus (SLE): Elevated serum concentrations of ET-1, s-thrombomodulin (TM), and sE-selectin reflect persisting endothelial cell activation in SLE, and point to an important role of ET-1 in the pathogenesis of internal organ involvement (Kuryliszyn-Moskal et al. 2008). The s-E-selectin, TM and s-VCAM-1 are significantly elevated in lupus nephritis (LN) with renal vascular lesions (VLS) than in LN without VLS. A positive correlation was found between TM and serum creatinine in patients with vascular lesions. Therefore, serum TM and s-VCAM-1 can be biomarkers of VLS in LN patients (Yao et al. 2008, Rho et al. 2008).

Autoimmune Thyroiditis: Autoimmune thyroiditis is multifactorial in etiology with genetic and environmental factors contributions. Patients with untreated Graves' disease (GD) show high serum level of sE-selectin, which correlated with the activity of the disease. The expression of ICAM-1 and VCAM-1 was increased in EC from patients from Graves' disease (GD) and Hashimoto's thyroiditis (HT). Results suggest that both the LFA-1/ICAM-1, ICAM-3 and VLA-4/VCAM-1 pathways could play a relevant role in autoimmune thyroid disorders (Marazuela et al. 1994). In patients with GD, the 721 G-A polymorphism was associated with an earlier age of GD onset (before age 40) and that the 1405A-G polymorphism could predispose to Graves ophthalmopathy. It was concluded that G241R and K469E amino acid substitutions in the ICAM1 molecule could influence the intensity/duration of the autoimmunity process and the infiltration of orbital tissues (Kretowski et al. 2003). Chen et al. (2008) suggested that common SELE variants may be associated with susceptibility to GD in Chinese population, though the limitation of sample size and multiple test problems exists (Chen et al. 2008).

Sjogren's Syndrome: CAMs are involved in the lymphoid cell infiltration of the salivary and lacrimal glands in Sjogren's syndrome (SS) patients. Biopsies from SS patients showed a marked expression of VCAM-1 and ICAM-1 in the venules surrounded by infiltrated CD4+ CD45RO+ T cells. E-selectin was expressed on vascular endothelium with weak intensity (Saito et al. 1993). Pisella et al. (2000) reported that a significant increase of HLA-DR and ICAM1 expression by epithelial cells was consistently found in patients with keratoconjunctivitis sicca (Sjogren syndrome). These markers were well correlated with each other and correlated inversely with tear break-up time and tear production. Cytokine-mediated up-regulation of VCAM-1 and ICAM-1 that facilitates the recruitment of VLA-4 and LFA-1 expressing T cells might contribute to lymphoid cell infiltration in the salivary and lacrimal glands in SS

44.6 CAMs in System Related Disorders

44.6.1 Gastric Diseases

CAMs mediate the extravasation of leukocytes and their accumulation in inflamed intestinal mucosa. Eosinophilic inflammation is a common feature of numerous eosinophil-associated gastrointestinal (EGID) diseases. Increased intestinal expression of E-selectin has been associated with multiple organ failure and an adverse outcome. VCAM-1 is not altered in in mucosa of patients with inflammatory bowel disease (IBD) regardless of the activity of the inflammatory process. In contrast, E-selectin was not detected in normal colonic mucosa or in colonic mucosa of patients with IBD. However, high levels of E-selectin were consistently found on endothelial surfaces in association with active inflammation in affected areas of colonic mucosa in patients with either ulcerative colitis or Crohn's colitis. In addition, E-selectin appeared to be present within neutrophils which had migrated into crypt abscesses in affected mucosa. Thus E-selectin may play an important role in facilitating leukocyte migration into sites of active IBD involvement (Koizumi et al. 1992)

ICAM-1 was expressed to a greater degree in ulcerative colitis (UC) specimens. Serum ICAM-1 levels in UC patients showed lower levels than those in the control group and were found to vary according to degree of clinical severity (Ogawa et al. 2008). Characterization of integrin expression on colonic eosinophils revealed that colonic CC chemokine receptor 3+ eosinophils express ICAM-1 counter-receptor integrins αL, αM, and β2. It appears that β2-integrin/ICAM-1-dependent pathways are integral to eosinophil recruitment in colon during GI inflammation associated with colonic injury (Forbes et al. 2006).

McCafferty et al. (1999) examined the role of P-selectin in intestinal inflammation in P-selectin deficient mice alone or in combination with either ICAM-1 or E-selectin and suggested that anti-adhesion therapy might play only a limited, beneficial role and often a detrimental role in intestinal inflammation. The sE-selectin levels of Crohn's disease patients with active disease are higher than those with remission of the disease. L-selectin does not change in patients with active disease compared to those with remission. Thus, determination of sE-selectin in children with Crohn's disease is of significance in estimation of inflammation activity (Adamska et al. 2007).

Khazen et al. (2009) investigated mutations in CAM genes in Tunisian patients, implicated in determining susceptibility to ulcerative colitis (UC) and Crohn's disease (CD). A significant increase in allele frequencies of 206 L of L-selectin and the associated genotype F/L was observed in patients with UC and CD compared with controls; the L206 allele and F/L206 genotype frequencies were significantly increased in UC patients with left-sided type; whereas, the F/L206 genotype was significant in CD patients with ileocolonic location. No significant differences in allele or genotype frequencies were observed for ICAM-1 K469E, E-selectin, and PECAM-1 polymorphisms between UC patients, CD patients, and controls. Khazen et al. (2009) suggest an association of inflammatory bowel disease with allele L206 of L-selectin gene, whereas genotype L/F was associated with a subgroup of UC (left-sided type) and CD patients with more extensive location of disease and stricturing behavior.

However, Vischer et al. (2008) did not reveal any difference in mRNA and protein expression levels for any construct or a major impact of missense variants on ICAM-1 biological function. Pulse-chase experiments showed that two variants, K469E and arg478 to trp (R478W), had a prolonged half-life compared with wildtype ICAM1, whereas two other variants, G241R and pro352 to leu (P352L), had a decreased half-life, implying differences in protein degradation.

Celiac Disease: Celiac disease is a chronic intestinal inflammatory disease that develops in genetically susceptible individuals after gluten ingestion. The ICAM-1 gene, located in the Celiac disease linkage region 19p13, encodes ICAM-1 involved in inflammatory processes. Increased levels of ICAM-1 were observed in intestinal biopsies and in sera of Celiac disease patients. In addition, an association between the ICAM1 polymorphism G241R and Celiac disease patients has been described in a French population.though, in spanish population results discard the importance of ICAM1 G241R in celiac disease (Dema et al. 2008).

Behçet Syndrome: Behçet's disease/syndrome (BD/BS) is a multisystemic inflammatory disorder of which oral aphthous ulceration is a major feature. CD3 and γδ T-cell expression and other adhesion molecules including VCAM-1 and ICAM-1 were upregulated, whereas CD40 showed little change in BD. The changes in cell-cell and cell-extracellular matrix interactions may affect cell homeostasis and participate in the formation of oral ulcers in BD (Kose et al. 2008). However, Demirkesen et al. (2008) found no significant differences between the BS and control groups in regard to E-selectin, P-selectin, VCAM-1, PNCAM-1 except for ICAM-1.

Systemic Sclerosis or Systemic Scleroderma: Systemic sclerosis or systemic scleroderma is a systemic autoimmune disease or systemic connective tissue disease that is a subtype of scleroderma. Severe fibrosis and increased expression of profibrotic cytokines are important hallmarks in the gastric wall of patients with systemic sclerosis (SSc; scleroderma). The CD4+/CD8+ T cell ratio is significantly increased in SSc specimens. T cells strongly express the activation markers VLA-4, LFA-1, and ICAM-1. Endothelial cells showed corresponding surface activation with strong expression of VCAM-1 and ICAM-1. These results provide the evidence that endothelial/lymphocyte activation leading to prominent CD4+ T cell infiltration may play a key pathogenetic role within the gastric wall of patients with SSc (Manetti et al. 2008). In patients with SSc with and without pulmonary arterial hypertension (PAH), serum sICAM-1, sVCAM-1, sP-selectin and sPECAM-1 levels were higher than in healthy donors (HD) at baseline and fell to normal values after 12 months of bosentan therapy. Endothelial activation occurs in SSc, and that changes in the T cell/endothelium interplay take place in SSc-associated PAH. Bosentan seems to be able to hamper these changes and restore T cell functions in these patients (Iannone et al. 2008).

44.6.2 Liver Diseases

Soluble adhesion molecules play a significant role in hepatitis. Biliary atresia (BA) is a congenital or acquired liver disease and one of the principle forms of chronic rejection of a transplanted liver allograft. In the congenital form, the common bile duct between the liver and the small intestine is blocked or absent. The acquired type most often occurs in the setting of autoimmune disease, and is one of the principle forms of chronic rejection of a transplanted liver allograft. The serum sE-selectin of BA patients was higher than that of controls. Subgroup analysis showed that there was an increase in sE-selectin levels of BA patients with jaundice compared to those without jaundice. Also, sE-selectin was positively correlated with serum alanine transferase (ALT), a marker for liver injury, but not with serum gamma glutamyl transpeptidase (GGT) (Vejchapipat et al. 2008).

Cholangitis without a modifier—from Greek chol-, bile + ang-, vessel + itis-, inflammation) is an infection of the bile duct (cholangitis). In secondary cholangitis, ICAM-1 expression is increased along with de novo VCAM-1 and E-selectin appearance on the endothelium of microvessels in chronic exacerbated cholangitis (Gulubova et al. 2008).

Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts (bile canaliculi) within the liver. Patients with PBC, primary sclerosing cholangitis and chronic active hepatitis (autoimmune) show significant increase in sICAM-1 compared with normal healthy subjects. Significant elevation in sICAM-1 is also detected in patients with inactive alcoholic cirrhosis, suggesting that impaired liver may, in part, account for the increased serum level in patients with autoimmune liver disease. In contrast, sE-selectin did not differ significantly from healthy controls. Although, peripheral blood mononuclear cells (PBMC) may be a source of sICAM-1, Thomson et al. (1994) suggested that PBMC may not be a significant source of sICAM-1 in this disease. The differential expression of CAMs in the liver is consistent with the suggestion of selectins involvement in neutrophil rolling in the vasculature and ICAM-1 in transendothelial migration and adherence to parenchymal cells (Essani et al. 1995).

Wu et al. (2009) investigated the relationships between the polymorphisms of E-selectin gene and plasma sE-selectin levels in relation to disease progression in a hepatitis B virus (HBV)-infected Chinese Han population. The frequency of C allele (AC or CC) of the A561C polymorphism was significantly increased in patients with liver cirrhosis (LC) compared to normal population. There was no difference in allele distribution of the G98T polymorphism. The A561C polymorphism of E-selectin gene may be associated with disease progression in patients with chronic HBV infection and control the expression of plasma soluble levels, while the G98T polymorphism may be related to fibrotic severity in Chinese population (Wu et al. 2009).

Mice with targeted deletion of the P-selectin gene developed unpolarized type 1/type 2 cytokine responses and severely aggravated liver pathology following infection pathogen Schistosoma mansoni. Liver fibrosis increased 6 fold, despite simultaneous induction of IFN-γ and increase in inflammation in absence of P-selectin. This suggested a critical role of P-selectin in the progression of chronic liver disease caused by schistosome parasites (Wynn et al. 2004).

44.6.3 Neuro/Muscular Disorders

Axonal degeneration was confirmed as the major pathological feature of critical illness polyneuropathy (CIP). Expression of E-selectin was significantly increased in endothelium of epineurial and endoneurial vessels, suggesting endothelial cell activation (Fenzi et al. 2003). Increasing evidence indicates that inflammatory responses are implicated in the pathogenesis of cerebral vasospasm after aneurismal subarachnoid hemorrhage (SAH). Murine SAH model provided the evidence of effective prevention of SAH-induced vasospasm by a mAb implied the possible role of E selectin in the pathogenesis of vasospasm after SAH (Lin et al. 2005).

Neuroinflammation is present in the substantia nigra (SN) of patients of Parkinson disease (PD). A large number of ICAM-1-positive reactive astrocytes have been observed in the SN of patients with neuropathologically confirmed PD, including three of familial origin. The ICAM-1-positive reactive astrocytes were mainly concentrated around residual neurons in areas of heavy neuronal loss and extracellular melanin accumulation (Miklossy et al. 2006). The sVCAM-1 plasma levels were higher in late onset Alzheimer's disease (LOAD) and vascular dementia (VD) compared with controls. Among patients (LOAD, VD, and not-dementia (CDND), sE-selectin levels were higher in individuals with most severe cerebrovascular disease on CT scan. Increased sVCAM-1 plasma levels in LOAD and VD suggest the existence of endothelial dysfunction in both types of dementia. Results support the possible role of E-selectin in the pathogenesis of cerebrovascular disease (Zuliani et al. 2008).

44.6.4 Acute Pancreatitis

Upregulation of ICAM-1, LFA-1, Mac-1 and subsequent leukocyte infiltration appears to be significant events of pancreatic and pulmonary injuries in Acute pancreatitis (AP) (Sun et al. 2006). Proinflammatory cytokines and oxidative stress seem to be involved in the development of local and particularly systemic complications in AP patients. Acute pancreatitis patients show VCAM-1 and P-selectin concentrations significantly lower and L-selectin concentrations significantly higher than the healthy subjects. Only E-selectin was significantly higher in severe than in mild disease (Pezzilli et al. 2008). Kleinhans et al. (2009) showed that the endothelial cell expression of PECAM-1, VCAM, E-selectin, and P-selectin was upregulated in severe porcine pancreatitis. In acute pancreatitis, plasma levels of sE-selectin and soluble thrombomodulin (sTM) serve as endothelial markers; the former is an endothelial activation marker, while the latter is an endothelial injury marker (Chooklin 2009; Ida et al. 2009).

44.6.5 Renal Failure

In patients affected by microscopic polyangiitis (MPA) and associated with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibodies (ANCA), higher sICAM-1 and sE-selectin levels during active phase and their slower decline during the treatment period, could be a prognostic risk factor for chronic renal failure development (Di Lorenzo et al. 2004; Musial et al. 2005). An increased level of sE-selectin in patients susceptible to restenosis supports a role for white blood cell/endothelial interaction in restenosis after angioplasty (Sainani and Maru 2005). The impairment of vascular endothelial function was obvious in uremic patients with maintaining hemodialysis (MHD). The changes of ICAM-1 and E-selectin could be accepted as biochemical criterions of vascular endothelial injury (Li et al. 2005). Diuresis, serum creatinine, urea, and enzyme elimination are pathological among patients with acute renal failure (ARF). Higher elimination rates of sICAM-1 and higher values of sE-selectin compared to patients without ARF indicated additional parameters for early signs of kidney damage (Dehne et al. 2008). Both circulating and urinary TNF-α levels are increased in inflammatory chronic renal diseases. TNF-α appeared to play a crucial role in the immunopathogenesis of nephritis by the induction of chemokine, ICAM-1 and VCAM-1 expression via the activation of the intracellular MAPK signaling pathway, which may contribute to macrophage and lymphocyte infiltration (Ho et al. 2008; Li et al. 2008).

SNPs in Selectin genes and IgA Nephropathy: Although intensive efforts have been made to elucidate the genetic basis of Ig A nephropathy (IgAN), genetic factors associated with the pathogenesis of this disease are not well understood. A case–control study, based on linkage disequilibrium among SNPs in selectin gene cluster on chromosome 1q24-25 revealed two SNPs in the E-selectin gene (SELE8 and SELE13) and six SNPs in the L-selectin gene (SELL1, SELL4, SELL5, SELL6, SELL10, and SELL11), that were significantly associated with IgAN in Japanese patients. SELE8 and SELL10 caused amino acid substitutions from His to Tyr and from Pro to Ser for His-to-Tyr substitutions; and SELL1 could affect promoter activity of the L-selectin gene. The TGT haplotype at these three loci was associated significantly with IgAN. These SNPs in selectin genes may be useful for screening populations susceptible to the IgAN phenotype. (Takei et al. 2002)

Transplant Rejection: Soluble adhesion molecules are not valuable markers for stable kidney graft (STx) rejection reaction. However, patients with chronic renal failure showed increased levels of adhesion molecules, which could reflect an impaired elimination (Alcalde et al. 1995). The expression levels of ICAM-1 and VCAM-1 show positive correlation with the severity of graft rejection and can provide evidence for early diagnosis and prevention of CR. Chronic allograft failure (CAF) is the major cause for late graft loss in renal transplantation. ICAM-1 polymorphisms may represent a predetermined genetic risk factor for CAF. This was substantiated by the polymorphism in exon 4 at the Mac-1 binding site and in exon 6 at fifth Ig-like domain (McLaren et al. 1999). Khazen et al. (2007) found no evidence for an association of any polymorphism with acute rejection in E- and L-selectin. During kidney reperfusion, E-selectin, ICAM-1, and VCAM-1 concentrations correlated positively with hypoxanthine concentrations during reperfusion, whereas concentrations of ICAM-1 correlated negatively with xanthine concentrations, indicating metabolic changes in renal tissue (Domanski et al. 2009).

44.6.6 Other Inflammatory Disorders

Serum CAM levels have been analyzed in many organ diseases, including diseases of nervous system, endocrine disorders and others. Immune dysfunction has been proposed as a mechanism for pathophysiology of autistic-spectrum disorders. Levels of sP-selectin and sL-selectin were significantly lower in patients than in controls. Furthermore, sP-selectin levels were negatively correlated with impaired social development during early childhood (Iwata et al. 2008). In multiple sclerosis and in its animal model experimental autoimmune encephalomyelitis (EAE), inflammatory cells migrate across the endothelial blood–brain barrier (BBB) and gain access to the CNS. The role of E- and P-selectin in this process has been controversial. Döring et al. (2007) suggest that absence of E- and P-selectin did neither influence the activation of myelin-specific T cells nor the composition of the cellular infiltrates in the CNS during EAE. Thus, E- and P-selectin are not required for leukocyte recruitment across BBB and the development of EAE in C57BL/6 and in SJL mice (Döring et al. 2007). No significant differences in allelic or genotypic frequency in all the SNPs (rs6133, rs4987310 and rs5368 substitutions) tested were found in the Italian population (Fenoglio et al. 2009).

The pathophysiology of cluster headache (CH) is supposed to involve the lower posterior part of the hypothalamus, the trigeminal nerve, autonomic nerves and vessels in the orbital/retro-orbital region. Remahl et al. (2008) compared serum levels of sICAM-1, sVCAM-1 and sE-selectin in patients with episodic CH and in patients with biopsy-positive giant cell arteritis (GCA), a vasculitic disorder of large and medium-sized arteries. Within the CH group, sICAM-1, sVCAM-1 and sE-selectin showed an increasing trend in remission compared with active cluster headache period, but sE-selectin only was significant. Remahl et al. (2008) suggest that cluster headache is not a vasculitic disorder of medium-sized arteries, but CH patients may have an immune response that reacts differently from that of healthy volunteers.

Adhesion molecules have a role in many vasculitic disorders. Compared to controls, Takayasu's arteritis (TA) patients had elevated levels of sE-selectin, sVCAM-1, and sICAM-1. Compared to controls, patients with inactive TA also had elevated levels of sE-selectin, sVCAM-1, and sICAM-1. There was no difference between active TA and controls. The sE-selectin had a trend towards increased levels in inactive versus active TA, but there was no difference in sVCAM-1 and sICAM-1 levels between the groups. Patients with inactive TA had elevated levels of sE-selectin, sVCAM-1, and sICAM-1 that might indicate persistent vasculopathy in clinically inactive disease (Tripathy et al. 2008).

44.6.7 Inflammation in Hereditary Diseases

Serum levels of sVCAM-1, sICAM-1, sTM, P-selectin, E-selectin and CRP levels as inflammation markers are increased in patients of β-thalassemia intermedia and not influenced by treatment (Kanavaki et al. 2009). Pseudoxanthoma elasticum (PXE) is a hereditary disorder predominantly affecting the skin, retina and vascular system. P-selectin concentrations were increased in male and female PXE patients and levels correlated with the ABCC6 gene status of the patients. Patients harboring two mutant ABCC6 alleles had 1.5-fold increased P-selectin concentrations in comparison to patients with at least one wild-type allele. E- and L-selectin levels were within normal range and the allelic frequencies did not differ between from controls. Elevated P-selectin levels in PXE patients are potentially due to oxidative stress and elevated protease activity in PXE (Götting et al. 2008).

Fabry disease, an X-linked systemic vasculopathy, is caused by a deficiency of α-galactosidase A resulting in globotriaosylceramide (Gb3) storage in cells. Accumulation of Gb3 in the vascular endothelium of Fabry disease is associated with increased production of reactive oxygen species (ROS) and increased expression of CAMs. Increased Gb3 induces expression of ICAM-1, VCAM-1, and E-selectin. Reduction of endogenous Gb3 by treatment of the cells with an inhibitor of glycosphingolipid synthase or α-galactosidase A led to decreased expression of adhesion molecules. This study indicates that excess intracellular Gb3 induces oxidative stress and up-regulates the expression of CAMs in vascular endothelial cells (Shen et al. 2008).

44.7 Role of CAMs in Cancer

Recent reports have expanded the concept that inflammation is a critical component of tumor progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumor microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumor cells have co-opted some of the signaling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development

44.7.1 Selectin Ligands in Cancer cells

Sialosyl Lewis a in Adhesion of Colon and other Cancers: The complexity of the tumor microenvironment has been revealed in the past decade. The CAMs in the process of inflammation are responsible for recruiting leukocytes onto the vascular endothelium before extravasation to the injured tissues. Some circulating cancer cells have been shown to extravasate to a secondary site using a process similar to inflammatory cells. The most studied ligands for CAMs expressed on cancer cells, s-Lewisa and s-Lewisx antigens, are shown to be involved in adhesion to endothelial cells by binding to E-selectin. This process, shared by inflammatory cells and cancer cells, may partially explain the link between inflammation and tumorigenesis. The adhesion of colon cancer cells to E-selectin can be directly affected by changes in the expression level of sialosyl Lea antigen. The specific lack of expression of sialosyl Lea carbohydrate structure on the surface of colon cancer cells completely abolished their adhesion to E-selectin. It is proposed that glycoproteins as well as gangliosides carrying sialosyl Lea structures, when properly exposed and present in high density on surface of cancer cells, can effectively support the adhesion of cancer cells to E-selectin (Klopocki et al. 1998; Kobayashi et al. 2007). In addition to endogenous ligands for L-, P-, and E-selectins ( Chap. 26,  27, and  28), several proteins are found in cancer cell lines or solid tumors that act as ligands for E, L, and P selectins. Selectin ligands present in cancers are:

(1) Glycodelin A (GdA) is primarily produced in endometrial and decidual tissue and secreted to amniotic fluid. GdA is expressed in ovarian cancer where it can act as an inhibitor of lymphocyte activation and/or adhesion (Jeschke et al. 2009); (2) The cysteine-rich fibroblast growth factor receptor (FGF-R) represents the main E-selectin ligand (ESL-1) on granulocytes. Hepatic stellate cells (HSC) are pericytes of liver sinusoidal endothelial cells, which are involved in the repair of liver tissue injury and angiogenesis of liver metastases. HSC express FGF-R together with FucT7 and exhibit a functional E-selectin binding activity on their cell surface (Antoine et al. 2009). (3) Although B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cell lines do not express the ligand PSGL-1, a major proportion of carbohydrate selectin ligand was carried by another sialomucin, CD43, in NALL-1 cells. CD43 plays an important role in extravascular infiltration of NALL-1 cells and the degree of tissue engraftment of BCP-ALL cells may be controlled by manipulating CD43 expression (Nonomura et al. 2008). (4) Thomas et al. (2009a) identified podocalyxin-like protein (PCLP) as an alternative selectin ligand. PCLP on LS174T colon carcinoma cells possesses E-/L-, but not P-, selectin binding activity. PCLP functions as an alternative acceptor for selectin-binding glycans. The finding that PCLP is an E-/L-selectin ligand on carcinoma cells offers a unifying perspective on the apparent enhanced metastatic potential associated with tumor cell PCLP overexpression and the role of selectins in metastasis (Thomas et al. 2009b). (5) E-selectin has been shown to play a pivotal role in mediating cell-cell interactions between breast cancer cells and endothelial monolayers during tumor cell metastasis. The counterreceptor for E-selectin was found as CD44v4. However, CD44 variant (CD44v) isoforms was functional P-, but not E-/L- selectin ligands on colon carcinoma cells. Furthermore, a ~180-kDa sialofucosylated glycoprotein(s) mediated selectin binding in CD44-knockdown cells. This glycoprotein was identified as carcinoembryonic antigen (CEA). CEA serves as an auxiliary L-selectin ligand, which stabilizes L-selectin-dependent cell rolling against fluid shear (Thomas et al. 2009b). Zen et al. (2008) identified a ~170 kDa human CD44 variant 4 (CD44v4) as E-selectin ligand, which has a high affinity for E-selectin via sLex moieties.

44.7.2 E-Selectin-Induced Angiogenesis

Angiogenesis plays an important role in a variety of pathophysiologic processes, including tumor growth and rheumatoid arthritis. Studies on capillary morphogenesis and angiogenesis in vitro have suggested a role for E-selectin in the process of differentiation into tube-like structures. Soluble E-selectin is a potent mediator of human dermal microvascular endothelial cell (HMVEC) chemotaxis, which is predominantly mediated through the Src and the phosphatidylinositiol 3-kinase (PI3K) pathways (Kumar et al. 2003). Gastrin-17 (G17) has marked proangiogenic effects in vivo on experimental gliomas and in vitro on HUVECs and transiently decreased the expression of E-selectin, but not P-selectin, whereas IL-8 increased the expression of E-selectin. Specific antisense oligonucleotides against E- and P-selectin decreased HUVEC tubulogenesis processes in vitro. This showed that gastrin has marked proangiogenic effects in vivo on experimental gliomas and in vitro on HUVECs. This effect depends in part on the level of E-selectin activation, but not on IL-8 expression/release by HUVECs (Lefranc et al. 2004).

44.7.3 E-Selectin in Cancer Cells

Adhesion molecules are thought to have a role in the host defense against carcinogenesis. Significantly increased P-selectin, s-VCAM-I and s-ICAM-I levels were observed in patients with bladder cancer, and s-VCAM-I levels correlated with tumor stage (Coskun et al. 2006). Selectins mediate attachment of leukocytes to activated endothelium as well as the adhesion reaction of tumor cells during malignancy (Borsig 2007). In a breast tumor xenograft model, the effect of combined TNF-α and IFN-γ therapy involved the selective destruction of the tumor vasculature and death of tumor cells. Concomitant with these changes RT-PCR analysis revealed the increase of stromal mRNA levels for a series of stromal cytokines, cytokine receptors including TNF-α, sICAM-1, VCAM-1, P-selectin, which could be implicated in the observed events (de Kossodo et al. 1995).

Squamous Cell Carcinomas: In order to evaluate the risk of postoperative haematogenic recurrence of esophageal squamous cell carcinoma (SCC) patients, Shimada et al. (2003) examined the preoperative serum levels of sE-selectin and pathological status of the patients. The patients with a high serum soluble E-selectin concomitant with expression of s-Lewis antigens had a significant risk of postoperative haematogenic recurrence. SCCs of sun-induced skin cancers are particularly numerous in patients on T cell immunosuppression. Blood vessels in SCCs did not express E-selectin, and tumors contained few cutaneous lymphocyte antigen (CLA+) T cells, the cell type thought to provide cutaneous immunosur-veillance. Clark et al. (2008) found that SCCs evade the immune response at least in part by down-regulating E-selectin and recruiting Treg cells.

Cutaneous T-Cell Lymphoma (CTCL): The CTCL is characterized by accumulation of malignant CD4+ T cells in the skin. In malignant T cells from Sezary syndrome (SS), a leukemic variant of CTCL, in dermal microvessels in mouse skin, Hoeller et al. (2009) found that SS cells rolled along dermal venules in a P-selectin- and E-selectin-dependent manner at ratios similar to CD4+ memory T cells from normal donors. Chemokine CCL17/TARC was sufficient to induce the arrest of SS cells in the microvasculature. Together, experiments suggested molecular adhesion cascade operant in SS cell homing to the skin in vivo. Patients with CTCL showed increased levels of sICAM-1 and sICAM-3 when compared with healthy individuals and patients with inflammatory dermatosis. The sE-selectin and sVCAM-1 levels were not affected (López-Lerma and Estrach 2009).

Hodgkin's Disease: Increased sICAM-1 and sE-selectin have been observed in Hodgkin's Disease/lymphoma (HD/HL) patients at diagnosis and sVCAM-1 at diagnosis correlated with both sICAM-1 and sE-selectin levels. Chemotherapy resulted in a significant decrease of sICAM-1 and sE-selectin (Syrigos et al. 2004). Serum sICAM-1 level increases at advanced stages of untreated multiple myeloma (MM) patients, but did not differ significantly from controls. A positive correlation of IL-6 appeared with sICAM-1 and sE-selectin (Uchihara et al. 2006). Epstein-Barr virus (EBV)-positive NK/T cells showed affinity to vascular components. EBV-positive NK lymphoma cells express ICAM-1 and VCAM-1 at much higher levels than those in EBV-negative T cell lines. Furthermore, NK lymphoma cell lines exhibited increased adhesion to cultured endothelial cells stimulated with TNF-α or IL-1β. The up-regulated expression of VCAM-1 on cytokine-stimulated endothelial cells can be important to initiate the vascular lesions (Kanno et al. 2008).

Non-small Cell Lung Cancer: Serum levels of ICAM-1 increased in advanced stage non-small cell lung cancer (NSCLC) patients, whereas sE-selectin levels were not significantly different from healthy controls Reports suggest that higher serum ICAM-1 can be useful for diagnosis while E-selectin levels have prognostic significance and could be a potential prognostic factor in NSCLC patients (Dowlati et al. 2008; Guney et al. 2008). The Cyfra 21–1 and sE-selectin showed good performance in detecting lung cancer from normal groups. However, Cyfra 21–1 was superior to sE-selectin in discriminating lung cancer from benign lung diseases (Swellam et al. 2008). Thyroid Cancer

Maspin, a serine protease inhibitor belonging to serpin family, is known as a tumor-suppressor protein and also exhibits an inhibitor effect on angiogenesis. Positive correlations were found for maspin positivity and lymph node metastases; E-selectin positivity and lymph node metastases, and P-selectin positivity and lymph node metastases and lymphovascular invasion. Correlations do exist between maspin, E- and P-selectin expressions with each other and with tumor stage. Inactive cytoplasmic maspin cannot act as a tumor suppressor. Expression of E- and P-selectins in tumor cells facilitates the occurrence of metastases, lymphovascular invasion, and perithyroidal soft tissue invasion. Further studies are needed to reveal detailed interactions between maspin, E-selectin, and P-selectin expression (Bal et al. 2008).

Primary Hyperparathyroidism: Patients with primary hyperparathyroidism (PHPT) have impaired vasodilation. Based on small number of patients, a study suggested that classic cardiovascular risk factors seem to be the main determinants for the high plasma levels of sE-selectin and vWF in PHPT. Together with unaltered thrombomodulin and sE-selectin levels, the vWF decrease in plasma after parathyroidectomy reflects a specific mechanism of its endothelial calcium- and/or PTH-stimulated secretion in some PHPT patients without risk factors (Fallo et al. 2006).

Colorectal Cancer: Plasma level of sP-selectin, sE-selectin and ICAM-1 were significantly higher in colorectal cancer (CRC) patients. The highest levels of sE-selectin and ICAM-1 were observed in patients with liver metastasis. There was no correlation between sP-selectin and sE-selectin, but a significant correlation was seen between sE-selectin and ICAM-1 in all patients. Plasma concentration of E-selectin and ICAM-1 may indicate tumor progression and liver metastasis (Dymicka-Piekarska and Kemona 2009; Sato et al. 2010).

The interaction between rE-selectin and CRC cells alters the gene expression profile of cancer cells. A DNA microarry analysis indicated that E-selectin-mediated alterations were significantly more pronounced in metastatic CRC variants SW620 and KM12SM than in the corresponding non-metastatic local SW480 and KM12C variants. The number of genes altered by E-selectin in metastatic variants was 10-fold higher than the number of genes altered in the corresponding local variants. Analysis indicated that E-selectin down regulated (at least by 1.6-folds) the expression of seven genes in a similar fashion, in both metastatic cells. Confocal microscopy indicated that E-selectin down-regulated the cellular expression of HMGB1 protein and enhanced the release of HMGB1 into the culture medium. The released HMGB1 in turn, activated endothelial cells to express E-selectin (Aychek et al. 2008).

The entrapment of malignant cells within the hepatic sinusoids and their interactions with resident non-parenchymal cells are considered very important for the whole metastatic sequence. In the sinusoids, cell connection and signaling is mediated by multiple cell adhesion molecules, such as the selectins. The three members of the selectin family, E-, P- and L-selectin, in conjunction with sialylated Lewis ligands and CD44 variants, regulate colorectal cell communication and adhesion with platelets, leucocytes, sinusoidal endothelial cells and stellate cells. Therefore, trials have already commenced aiming to exploit selectins and their ligands in the treatment of benign and malignant diseases. Multiple pharmacological agents have been developed that are being tested for potential therapeutic applications (Schnaar et al. 2008; Paschos et al. 2010; Zigler et al. 2010).

44.7.4 Metastatic Spreading

The degree of selectin ligand expression by cancer cells is well correlated with metastasis and poor prognosis for cancer patients. Initial adhesion events of cancer cells facilitated by selectins result in activation of integrins, release of chemokines and are possibly associated with the formation of permissive metastatic microenvironment. While E-selectin is one of the initiating adhesion events during metastasis, it is becoming apparent that P-selectin and L-selectin-mediated interactions significantly contribute to this process as well (Gout et al. 2008; Läubli and Borsig 2010).

E-Selectin in Progression of Metastasis of Breast Cancer: Extravasation of cancer cells is a pivotal step in the formation of hematogenous metastasis. Extravasation is initiated by the loose adhesion of cancer cells to endothelial cells via an interaction between endothelial selectins and selectin ligands expressed by the tumor cells. Metastatic spreading is a dreadful complication of neoplastic diseases that is responsible for most deaths due to cancer. It consists in the formation of secondary neoplasms from cancer cells that have detached from the primary site. Leukocytes and tumor cells use E-selectin binding ligands to attach to activated endothelial cells expressing E-selectin during inflammation or metastasis. The formation of these secondary sites is not random and several clinical observations indicate that the metastatic colonization exhibits organ selectivity. This organ tropism relies mostly on the complementary adhesive interactions between cancer cells and their microenvironment. E-selectin and sLewis antigens might play important role in breast tumor, lymph node and liver metastasis. High levels of sE-selectin have been reported in melanoma and some epithelial tumors, especially in colorectal carcinoma. But sE-selectin may not be used as a predictive marker of metastasis in colorectal carcinoma, though high levels of sE-selectin may support diagnosis of liver metastasis (Uner et al. 2004; Eichbaum et al. 2004). It appeared that serum levels of sE-selectin are associated with the clinical course of liver metastases from breast cancer. Eichbaum et al. (2004) observed a possible trend for certain unfavorable prognostic parameters (e.g., young women, low-graded tumors, human epidermal growth factor receptor 2 over-expression) that could be related to higher serum levels of sE-selectin.

Role of E-Selectin in Diapedesis of Cancer Cells: Diapedesis is a vital part of tumor metastasis, whereby tumor cells attach to and cross the endothelium to enter the circulation. E-selectin was found to regulate initial attachment and rolling of colon cancer cells and also the subsequent diapedesis through the endothelium. Evidence indicates that E-selectin-dependent paracellular extravasation is independent of ICAM and VCAM and that it requires the activation of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase downstream of E-selectin. Studies establish the role of E-selectin in diapedesis of circulating cancer cells (Tremblay et al. 2008; Woodward 2008).

Polymorphisms within E-selectin gene, especially the S128R polymorphism, may increase the risk of metastases by facilitating adhesion of tumor cells to endothelium. Blood DNA from patients treated for stage II or III colorectal cancer (CRC) and from healthy controls was assessed for three polymorphisms within E-selectin gene (S128R, G98T and L554F) and one within the P-selectin gene (V640L). The S128R polymorphism was detected in 22.3 % patients and was correlated with G98T polymorphism. In multivariate analysis, the S128R polymorphism was associated with shorter event-free survival (EFS) and overall survival (OS) in whole population, in patients with stage II CRC, and in patients with stage III CRC. L554F and V640L polymorphisms had no prognostic value. The S128R polymorphism is a constitutional factor associated with a higher risk of relapse and death in patients treated for CRC and its detection may permit better selection of patients suitable for adjuvant therapy, especially among those with stage II disease (Hebbar et al. 2009).

P-selectin Deficiency Attenuates Tumor Growth and Metastasis: Metastasis is thought to involve the formation of tumor-platelet-leukocyte emboli and their interactions with the endothelium of distant organs. A link between these observations shows that P-selectin, which normally binds leukocyte ligands, can promote tumor growth and facilitate the metastatic seeding of a mucin-producing carcinoma. P-selectin-deficient (P-sele−/−) mice showed three potential pathophysiological mechanisms: (1) intravenously injected tumor cells home to the lungs of P-sele−/− mice at a lower rate; (2) P-sele−/− mouse platelets fail to adhere to tumor cell-surface mucins; and (3) tumor cells lodged in lung vasculature after intravenous injection often are decorated with platelet clumps, and these are markedly diminished in P-selectin−/− animals (Kim et al. 1998). However, the surgical procedure did not totally eliminate the factors responsible for platelet activation and did not normalize platelet activation (Dymicka-Piekarska et al. 2005; Hanley et al. 2006).

Role of Sialyl-Lewis Antigens: During inflammation, E- and P-selectins appear on activated endothelial cells to interact with leukocytes through sialyl-Lewis X (sLex) and sialyl-Lewis A (sLea). These selectins can also interact with tumor cells in a sialyl-Lewis-dependent manner and hence, they are thought to play a key role in metastasis. Diverting the biosynthesis of sialyl-Lewis antigens toward nonadhesive structures is an attractive gene therapy for preventing the hematogenous metastatic spread of cancers. The transduced α1,2-fucosyltransferase-1 (FUT1) efficiently fucosylated the P-selectin ligand PSGL-1 without altering P-selectin binding (Mathieu et al. 2004).

The metastasis of cancer cells and leukocyte extravasation into inflamed tissues share common features. Carbohydrate antigen sLea (CA19-9) is the most frequently applied serum tumor marker for diagnosis of cancers in the digestive organs. The normal counterpart of the determinant, namely disialyl-Lea is predominantly expressed in non-malignant epithelial cells of the digestive organs. The disialyl-Lea determinant carries one extra sialic residue attached through a 2 → 6 linkage to GlcNAc moiety compared to cancer-associated sLea, which carries only one 2 → 3 linked sialic acid residue (monosialyl Lewis A) (Fig. 44.3). Disialyl-Lea in normal epithelial cells serves as a ligand for immunosuppressive receptors such as sialic acid binding Ig-like lectins (siglec-7 and -9) expressed on resident monocytes/macrophages and maintains immunological homeostasis of mucosal membranes in digestive organs. Epigenetic silencing of a gene for a 2 → 6 sialyl-transferase in the early stages of carcinogenesis results in impairment of 2 → 6 sialylation, leading to incomplete synthesis and accumulation of sLea, which lacks the 2 → 6 linked sialic acid residue, in cancer cells. Simultaneous determination of serum levels of sLea and disialyl-Lea, and calculation of the sLea/disialyl-Lea ratio provides information useful for excluding a false-positive serum diagnosis. During cancer progression in locally advanced cancers, tumor hypoxia induces transcription of several glyco genes involved in sLea synthesis. Expression of the determinant, consequently, is further accelerated in more malignant hypoxia-resistant cancer cell clones, which become predominant clones in advanced stage cancers and frequently develop hematogenous metastasis. sLea, as well as its positional isomer sLea, serves as a ligand for vascular E-selectin and facilitates hematogenous metastasis through mediating adhesion of circulating cancer cells to vascular endothelium. Patients having both strong sLea expression on cancer cells and enhanced E-selectin expression on vascular beds are at a greater risk of developing distant hematogenous metastasis (Kannagi 2007). In a human-mouse model, the selectin ligand s-Lea is involved in in vivo extravasation of colorectal carcinoma (CRC) cells. Highly metastatic CRC cells expressing high levels of s-Lea extravasate more efficiently than non-metastatic CRC cells expressing low levels of s-Lea. Down-regulating the expression of s-Lea in CRC cells by genetic manipulations, significantly reduced CRC extravasation. The arrest and adhesion of CRC cells, and possibly of other types of cancer cells as well, to endothelium depend on the expression of the selectin ligand sLea by the tumor cells (Ben-David et al. 2008). 3'-Sulfo-Lea is known to be the potent ligand of E-selectin which is important in cell adhesion and migration. The serum 3'-sulfo-Lea can provide important information in patients with primary gastric cancer, which might be useful as a predictive marker especially for the detection of tumor metastasis (Zheng et al. 2009).
Fig. 44.3

Structures of three carbohydrate determinants, disialyl Lewis x (Lex), sialyl Lewis a and Lewis a (Lea). In panel, note that the only difference between the three determinants is the linkage of sialic acid residues. The α(2 → 6) sialic acid residue in disialyl Lea is synthesized by a sialyltransferase ST6GalNAcVI, which shows a significant decrease in its mRNA level upon malignant transformation

Specialized carbohydrates modified with sLex antigens on leukocyte membranes are ligands for selectin adhesion molecules on activated vascular endothelial cells at inflammatory sites. The sLex expression of invasive micropapillary carcinoma was higher than that of invasive ductal carcinoma, which was also associated with lymph node metastasis. E-selectin combined with sLex might play an important role in lymph node metastasis in invasive micropapillary carcinoma. The expression pattern of sLex in invasive micropapillary carcinoma suggested that the reversal of cell polarity of invasive micropapillary carcinoma might be as an important factor for the morphogenesis and possibly the pathogenesis, especially their higher rates of lymph node metastasis (Wei et al. 2010). The activity of core 2 β1,6 N-acetylglucosaminyltransferase (C2GnT1) in leukocytes greatly increases their ability to bind to endothelial selectins. C2GnT1 is essential for the synthesis of core 2-branched O-linked carbohydrates terminated with sLex (C2-O-sLex). E-selectin and its ligand-sLex are closely correlated with the metastasis of hepatocellular carcinoma. C2-O-sLex is a potentially useful early predictor of metastasis (Zhang et al. 2002). The expression profiles of C2-O-sLex in the malignant progression and metastasis of colorectal adenocarcinomas is upregulated in colorectal adenocarcinomas and metastatic liver tumors (St Hill et al. 2009).

44.7.5 Survival Benefits of Heparin

Endothelial P-Selectin as a Target of Heparin Action: Metastasis can be effectively inhibited by the anticoagulant heparin in different tumor models. At the cellular level, many of the antimetastatic effects of heparin in vivo are due to its action on P-selectin-mediated binding. Ludwig et al. (2007) addressed the potential contribution of endothelial P-selectin expression to adhesive events between the microvasculature and melanoma cells in vivo. Heparin not only inhibits P-selectin-mediated melanoma cell rolling but also attenuates melanoma metastasis formation in vivo, supporting the concept that endothelial P-selectin expression may represent an additional target of heparin in experimental melanoma lung metastasis (Ludwig et al. 2007). The low molecular weight heparin (LMWH) significantly improved colonic inflammation in rats with trinitrobenzene sulphonic acid (TNBS) induced colitis. The effect is possibly related to inhibition of proinflammatory cytokine IL-8, but not involved platelet surface P-selectin expression (Xia et al. 2004). The survival benefits in patients with cancer treated with LMWH may result from a LMWH-mediated effect on the immune system or on the cross-talk between platelets and tumor cells. However, survival observed with LMWH in patients with cancer apparently cannot be explained by a LMWH effect on these circulating markers (Di Nisio et al. 2005). Nonetheless, in vivo anti-metastatic effects of heparins reflect their action on P-selectin-mediated binding. Therefore, these commonly used anticoagulants widely differ in their potential to interfere with P-selectin mediated cell binding. Importantly, the superior inhibitory capacity on P-selectin function of unfractionated heparin and LMWH nadroparin as opposed to LMWH enoxaparin and synthetic heparin pentasaccharide fondaparinux strongly correlated to the inhibitory potency of each in inhibiting experimental lung metastasis in vivo. Hence, P-selectin inhibition constitutes a valuable feature to identify anticoagulants that are suitable for anticancer therapy (Ludwig et al. 2006). Stevenson et al. (2005) studied metastasis inhibition by clinically relevant levels of various heparins and investigated the structural basis for selectin inhibition differences. Five clinically approved heparins were evaluated for inhibition of P-selectin and L-selectin binding to carcinoma cells and showed differing abilities to inhibit selectins, likely explained by size distribution. It should be possible to size fractionate heparins and inhibit selectins at concentrations that do not have a large effect on coagulation. Gao et al. (2005) prepared periodate-oxidized, borohydride-reduced heparin (RO-heparin) and tested its anticoagulant and anti-inflammatory activities. Compared with heparin, RO-heparin had greatly reduced anticoagulant activity. Intravenous administration of this compound led to reduction in the peritoneal infiltration of neutrophils in a mouse acute inflammation model. In vitro studies showed that the effect of RO-heparin on inflammatory responses was mainly due to inhibiting the interaction of P-selectin with its ligands. These results indicate that RO-heparin may be a safer treatment for inflammation than heparin, especially when selectin is targeted.

To clarify the mechanism of heparin antimetastatic activity, several biological effects are being investigated. Cancer progression and metastasis are associated with enhanced expression of heparanase, which is inhibited efficiently by heparin. Heparin is also a potent inhibitor of selectin-mediated interactions. P- and L-selectin were shown to contribute to the early stages of metastasis, which is associated with platelet-tumor cell thrombi formation. Low anticoagulant heparin preparations still inhibited metastasis efficiently indicating that anticoagulation is not a necessary component for heparin attenuation of metastasis. Modified heparins characterized for heparanase inhibitory activity are also potential inhibitors of selectins. Selectin inhibition is a clear component of heparin inhibition of metastasis. The contribution of selectin or heparanase inhibition by heparin can provide evidence about its antimetastatic activity (Borsig 2007). One of the mechanisms by which heparin inhibits metastasis is by blocking the P-selectin-based interaction of platelets with tumor cell. The sulfate groups at C6/N and especially C6, but not C2 and C3, of heparin play a critical role in P-selectin recognition and that 2-O,3-O-desulfated heparin can block P-selectin-mediated A375 human melanoma cell adhesion. Thus chemical modification of heparin, especially 2-O,3-O-desulfation, may result in a therapeutic agent that is anti-metastatic because it blocks unwanted P-selectin-dependent adhesion but that lacks dose-limiting anticoagulant effects (Wei et al. 2005).

Heparin-Induced Thrombocytopenia: The pathophysiology of heparin-induced thrombocytopenia (HIT) is a complex process which involves platelets, vascular endothelium, and leukocytes. The activation products from these sites also contribute to the activation of coagulation and to the fibrinolytic deficit. Many of the markers of hemostatic activation processes have been found to be at increased levels during acute phases of the HIT syndromes. Since the pathophysiology of HIT involves the activation of platelets, endothelium, and leukocytes, it is expected that activation products related to these hemostatic systems, including soluble selectins, will also be increased in circulating blood. These alterations may provide an index of the pathophysiologic process. Fareed et al. (1999) reviewed on the circulating levels of P-, E-, and L-selectins in HIT patients and their modulation after therapeutic intervention. With the availability of recombinant hirudin, it is now possible to provide alternate anticoagulants to HIT patients. However, Fareed et al. (1999) suggest that the immunoactivation of platelets and other cells may require additional adjunct therapeutic approaches.

44.8 Adhesion Proteins in Transplantation

Activated protein C (APC) is the major physiological anti-coagulant with concomitant anti-inflammatory properties. Turunen et al. (2005) suggest that APC has an anti-inflammatory role in I/R injury in clinical renal transplantation (Turunen et al. 2005). Bimosiamose prolongs survival of kidney allografts. Binding of the P-, L-, and E-selectins to sLe X retards circulating leukocytes, thereby facilitating their attachment to the blood vessels of allografts. Selectin inhibitor bimosiamose (BIMO) inhibits the rejection process of kidney allografts in a rat model in association with reduced intragraft expression of P-selectin glycoprotein ligand-1, CX(3)CL1, CCL19, CCL20, and CCL2. Thus, BIMO blocks allograft rejection by reduction of intragraft expression of cytokines and chemokines (Langer et al. 2004).

Brain death (BD), a significant antigen-independent process, the donor-related injury up-regulates variety of inflammatory mediators in peripheral organs. One of the immediate responses is the expression of selectins by endothelial cells of the transplanted tissues, which in turn trigger a cascade of nonspecific events that may enhance host alloresponses. Using a rat model in which donor BD accentuates subsequent renal allograft injury, Gasser et al. (2005) tested the effects of therapy with rPSGL-Ig alone, or in combination with sirolimus (SRL) and cyclosporin A. It was found that in contrast to the effects of standard doses of SRL or cyclosporine, rPSGL-Ig decreased inflammation in the early posttransplant period such that lower doses of maintenance immunosuppression were sufficient to maintain long-term graft function.

Intestinal transplantation (ITx) is severely limited by ischemia-reperfusion (I/R) injury. T lymphocyte is an important regulatory cell in this inflammatory process (Farmer et al. 2005a). rPSGL-Ig treatment leads to marked improvement in the outcome. The mechanism of action seems to involve the blockade of neutrophil and lymphocyte infiltration that leads to a decreased inflammatory response possibly driven by Th2 cytokines (Farmer et al. 2005b).

It was suggested that liver transplantation and liver resection, together with portal clamping time, might be a potential stimulus for platelet activation. Becker et al. (2004) indicated that neither liver transplantation nor liver resection influences GPIIb/IIIa and P-selectin expression on circulating platelets (Becker et al. 2004).

44.9 Inflammation During Infection

44.9.1 Microbial Pathogens

Endothelial activation contributes significantly to the systemic inflammatory response to bacteraemia. Release of soluble endothelial markers into the circulation has been demonstrated together with elevated plasma levels of CAMs and has been reported in bacteraemic patients. It has been proposed that the infection of endothelial cells with Staphylococcus aureus, Streptococcus sanguis, or Staphylococcus epidermidis induces surface expression of ICAM-1 and VCAM-1 and monocyte adhesion. In general, leukocyte/endothelial cell interactions such as capture, rolling, and firm adhesion should be viewed as a series of overlapping synergistic interactions among adhesion molecules resulting in an adhesion cascade. These cascades thereby direct leukocyte migration, which is essential for the generation of effective inflammatory responses and the development of rapid immune responses (Golias et al. 2007). Helicobacter pylori is a common bacterial pathogen that infects world's population up to 50 %. Carbohydrate components on H. pylori (sequences related to Lex or Lea antigens) are responsible for the persistent inflammation through interactions with leukocyte-endothelial adhesion molecules of the host. H. pylori isolates from patients with chronic gastritis, duodenal ulcer and gastric cancer interact with E- and L-selectins (Galustian et al. 2003). Expression of E-selectin was specifically upregulated in H. pylori-induced gastritis but not in gastritis induced by acetylsalicylic acid or pouchitis. The upregulated E-selectin expression was localized to the gastric mucosa rather than being a systemic response to the infection (Svensson et al. 2009).

Although mice with mutations in individual selectins showed no spontaneous disease and had a mild or negligible deficiencies of inflammatory responses, Bullard et al. (1996), in contrast, found that mice with null mutations in both endothelial selectins (P and E) develop a phenotype of leukocyte adhesion deficiency characterized by mucocutaneous infections in response to intraperitoneal S. pneumoniae peritonitis. These mice provide strong evidence for the functional importance of selectins in vivo (Bullard et al. 1996). Anthrax lethal toxin (LT), a key virulence factor of Bacillus anthracis, enhanced VCAM-1 expression on primary human endothelial cells suggesting a causative link between dysregulated adhesion molecule expression and the poor immune response and vasculitis associated with anthrax. Results suggest that LT can differentially modulate NF-kB target genes and highlight the importance of VCAM-1 enhancement (Warfel and D'Agnillo 2008). Vascular endothelium stimulation in vitro that lead to the upregulation of CAMs is known for the pathogenic spirochaetes, including rLIC10365 of Leptospira interrogans. The recombinant proteins of L. interrogans in E. coli as a host were capable to promote the upregulation of ICAM-1 and E-selectin on monolayers of HUVECS. In addition, pathogenic and non-pathogenic Leptospira are both capable to stimulate endothelium E-selectin and ICAM-1, but the pathogenic L. interrogans serovar Copenhageni strain promoted a higher activation than the non-pathogenic L. biflexa serovar Patoc (Atzingen et al. 2009; Gómez et al. 2008). Chlamydia pneumoniae has been associated with cardiovascular disease and atherosclerosis. To determine the ability of C. pneumoniae to elicit inflammation, Högdahl et al. (2008) infected human coronary artery endothelial cells (HCAEC) with C. pneumoniae. Secretion of IL-8, MCP-1, and ICAM-1 was significantly increased after C. pneumoniae infection of HCAEC in comparison with uninfected controls, where as release of E-selectin or MMP-1did not change. This suggested that C. pneumoniae initiates and propagates vascular inflammation in ways that contribute to coronary artery disease (Högdahl et al. 2008).

CAMs in Gingival Crevicular Fluid: The sICAM-1, sVCAM-1, and sE-Selectin are present in gingival crevicular fluid (GCF) and changes in their levels may be a sensitive indicator to differentiate healthy sites from those with periodontitis (Hannigan et al. 2004; Tamai et al. 2007). Porphyromonas gingivalis is a Gram-negative bacterium that is an important etiologic agent of human adult periodontitis. E. coli LPS and isoforms of P. gingivalis LPS were potent in stimulating the expression of inflammatory markers, with E. coli LPS being more potent (Liu et al. 2008). DNA samples from blood of periodontitis patients genotyped for E-selectin Ser128Arg and L-selectin Phe206Leu revealed a significant difference in the Ser128Arg polymorphism of E-selectin, but not in L-selectin, between periodontal patients and controls; the 128Arg allele was present more frequently in patients. Houshmand et al. (2009) suggested that Ser128Arg polymorphism of E-selectin might contribute to the susceptibility of Iranian individuals to periodontitis.

CAMs in Subjects with HIV Disease: Swingler et al. (2003) suggested that while both soluble CD23 and ICAM1 promote resting cell HIV1 infection, productive infection of cycling cells requires soluble ICAM1. Swingler et al. (2003) noted that these results may explain in part the existence of a resting T-cell reservoir infected with HIV-1. Subjects with HIV disease have multiple risk factors for cardiovascular disease, including elevated levels of ICAM-1 and VCAM-1. Many of the variables associated with ICAM-1 and VCAM-1 levels can be related to their impact on inflammation (Melendez et al. 2008). The LFA-1, ICAM-1, and ICAM-3 are enriched at virological synapse (VS). The cognate adhesion molecule interactions at VS are important for HIV-1 spread between T cells (Jolly et al. 2007).

44.9.2 Yeasts and Fungi

Zuccarello et al. (2002) described a distinct form of familial chronic mucocutaneous candidiasis characterized by early-onset infections by different species of Candida, restricted to the nails of the hands and feet and associated with low serum concentration of ICAM-1. Phan and Filler (2009) measured the effects of C. albicans on the endothelial cell production of E-selectin and TNF-α in vitro. During invasive pulmonary aspergillosis, A. fumigatus hyphae invade the abluminal endothelial cell surface, whereas they invade the luminal endothelial cell surface during haematogenous dissemination. Infection with hyphae stimulates endothelial cells to synthesize E-selectin, VCAM-1, IL-8, and TNF-α in vitro. In neutropenic mice infected with wild-type A. fumigatus, increased pulmonary expression of E-selectin and TNF-αoccurred only when neutropenia had resolved. In nonneutropenic mice immunosuppressed with corticosteroids, A. fumigatus stimulated earlier pulmonary expression of E-selectin and VCAM-1, while expression of ICAM-1 and TNF-α was suppressed. In both mouse models, expression of E-selectin was associated with high pulmonary fungal burden, angioinvasion, and neutrophil adherence to endothelial cells (Chiang et al. 2008; Kamai et al. 2009).

44.9.3 Parasites and Amoeba Falciparum Malaria

Significant differences are observed between falciparum malaria patients and the healthy people in term of levels of both sE-selectin and thrombomodulin (TM). The levels of both sE-selectin and TM correlated positively with temperature, levels of IFN-γ and levels of TNF-α; and negatively with hemoglobin levels. Trends of positive correlations were observed between sP-selectin or vWF and temperature (Matondo et al. 2008). Evidence from autopsy and in vitro binding studies suggests that adhesion of erythrocytes infected with Plasmodium falciparum to the human host ICAM-1 receptor is important in the pathogenesis of severe malaria. Fernandez-Reyes et al. (1997) identified a mutation (K29M) in the ICAM1 gene, which they designated ‘ICAM1 Kilifi,’ that was associated with susceptibility to cerebral malaria with relative risks of 2.23 and 1.39 for homozygotes and heterozygotes, respectively. The available epidemiological, population genetic and functional evidence link ICAM-1(Kilifi) to severe malaria susceptibility (Fry et al. 2008; Cojean et al. 2008).

Increased serum concentrations of soluble sICAM-1, CD54 and of soluble E-, but not soluble P- and L-selectins were detected in Malagasy patients living in hyperendemic focus of Schistosoma mansoni. Serum levels of ICAM-1 were significantly correlated with the disease severity (Esterre et al. 1998). Studies in several models of inflammation have underscored the importance of P- and E-selectins in the migration of T cells to inflamed tissues. CD4+ T cells recruited to the cutaneous compartment during infection with Leishmania major express P- and E-selectin ligands. Results suggest that by blocking P- and E-selectins, the immune pathology associated with cutaneous leishmaniasis might be ameliorated without compromising immunity to infection (Zaph and Scott 2003). Invasive amebiasis offers a new model that poses an inadequate immune response leading to a continuous and prolonged activation of endothelial cells (ECs) by amebas, amebic molecules and cytokines, leading to necrosis. Hyperactivated endothelial cells continuously express ICAM-1 and E-selectin, pro-coagulant molecules (tissue factor, vWF, and the plasminogen activator inhibitor), resulting in ever greater inflammation and thrombosis (Campos-Rodríguez et al. 2009) Sepsis

Sepsis is a multifactorial, and often fatal, disorder typically characterized by widespread inflammation and immune activation with resultant endothelial activation. Though bacterial sepsis is most common, sepsis occurs with fungal, parastic and mycobacterial organisms. During bacterial sepsis in vivo, in wild-type mice and mice with E-, P-, or E-/P-selectin deficiencies, a phenotypic abnormality in E-selectin-deficient mice suggested that E- and P-selectin are important in the host defense against S. pneumoniae infection (Munoz et al. 1997). P-selectin is an important mediator of eosinophil recruitment to the cornea from limbal vessels to the corneal stroma, suggesting that P-selectin interactions may be potential targets for immunotherapy in eosinophil-mediated ocular inflammation (Kaifi et al. 2000).

Staphylococcus aureus is one of the most significant pathogens in human sepsis and endocarditis. Peptidoglycan induced surface expression of EC inflammation markers ICAM-1 and VCAM-1, which supported the adhesion of monocytes to these ECs (Mattsson et al. 2008). Teoh et al. (2008) assigned adiponectin as a modulator of survival and endothelial inflammation in experimental sepsis and a potential mechanistic link between adiposity and increased sepsis. Newborn infants with clinical diagnosis of sepsis demonstrated significantly higher plasma sE-selectin levels in infected infants. Infants with gram-negative sepsis had higher sE-selectin levels than did those with gram-positive sepsis. C-reactive protein was the best test for diagnosis of neonatal sepsis (Zaki and el-Sayed 2009).

Hofer et al. (2008) compared two different models of sepsis LPS-induced endotoxemia and cecal ligation perforation (CLP) bacteremia in rats with respect to changes in endothelial expression of CAMS as a marker for capillary breakdown of the blood brain barrier. Increased ICAM-1 expression might be an early factor involved in these pathogenic events. Although the role of PECAM-1 could not be determined, it was possible to show its expression on cerebral endothelium in all groups (Hofer et al. 2008). In mouse models of sepsis, Shapiro et al. (2009) demonstrated increased circulating levels of sE-selectin, sICAM-1, sVCAM-1 and sP-selectin at 24 h, while CLP was associated with increased levels of sE-selectin alone. In real-time PCR, mRNA levels for P-selectin, ICAM-1 and PAI-1 were increased in skin from endotoxemic mice. In CLP, mRNA levels for P-selectin, ICAM-1, E-selectin and PAI-1 were elevated, while VCAM-1 expression was reduced in skin. Most, but not all of these changes correlated with alterations in immunohistochemical staining (Shapiro et al. 2009).

44.10 Action of Drugs and Physical Factors on CAMS

The field of selectin inhibition has matured significantly in recent years in the ability to inhibit selectin/ligand interactions with drug-like molecules and to demonstrate disease modification in human trials. A comprehensive review of new developments in the field of selectin inhibition through discussion of patents/patent applications from 2003 to August 2009 has been reported by Bedard and Kaila (2010)

44.10.1 Inhibitors of Gene Transcription

Treatment of human endothelial cells with cytokines such as IL-1, TNF-α or IFN-γ induces the expression of specific leukocyte adhesion molecules on the endothelial cell surface. Interfering with either leukocyte adhesion or upregulation of adhesion protein is an important therapeutic target as evidenced by the potent anti-inflammatory actions of neutralizing antibodies to these ligands in various animal models and in patients. The induction of E-selectin, VCAM-1, and ICAM-1 genes requires the transcription factor NF-κB. Pharmaceutical agents, which prevent the induced expression of one or more of cell adhesion molecules on endothelium, might be expected to provide a novel mechanism to attenuate the inflammatory responses associated with chronic inflammatory diseases. E-selectin expression is induced on the endothelial cell surface of vessels in response to inflammatory stimuli but is absent in the normal vessels. Thus, E-selectin is an attractive molecular target, and high affinity ligands for E-selectin could be powerful tools for the delivery of therapeutics and/or imaging agents to inflamed vessels. Zimmerman and Blanco (2008) reviewed the structure and regulation of LFA-1 and different classes of inhibitors that interfere LFA-1/ICAM-1 interactions. Alicaforsen (ISIS 2302), an antisense to ICAM-1, designed to inhibit ICAM-1 expression did not reveal significant effect in Crohn's disease. However, topical enemas for ulcerative colitis demonstrated some effect in secondary outcomes, and initial studies in pouchitis are promising (Philpott and Miner 2008). ICAM-1 antibody (UV3) was highly effective at slowing the growth of tumors and/or prolonging survival in SCID mice xenografted with human multiple myeloma, lymphoma, melanoma and other cell lines (Brooks et al. 2008). A structurally diverse collection of small molecule inhibitors has been characterized and developed either to bind the IDAS site of αL I-domain or to the MIDAS of the β2 I-like domain.

44.10.2 Anti-NF-kB Reagents

CAMs play important roles in a critical step of tumor metastasis and arrest of tumor cells onto the venous or capillary bed of the target organ. In this process, IL-1β induces nuclear translocation of NF-kB in HUVE cells, followed by induction of cell surface expression of E-selectin, ICAM-1, and VAM-1, and subsequent adhesion of those cancer cells expressing sialyl LeX antigen, which is a ligand to E-selectin. The adhesion of tumor cells to IL-1β-treated HUVE cells can be inhibited by anti-NF-kB reagents such as N-acetyl L-cysteine, aspirin, or pentoxifylline. These observations indicate the involvement of NF-kB in cancer metastasis and the feasibility of using anti-NF-kB reagents in preventing metastasis (Tozawa et al. 1995). Incubation of HUVEC with N,N,N-trimethylsphingosine (TMS) resulted in a dose-dependent inhibition of IL-1β-induced E-selectin expression. Sphingosine or N,N-dimethylsphingosine had no effects on the expression. This inhibitory effect of TMS on IL-1β-dependent endothelial cell activation may partly explain the known anti-inflammatory or anti-metastatic effect of TMS in vivo (Masamune et al. 1995). Cimetidine inhibits the expression of E-selectin on vascular endothelial cells in gastric- and colorectal cancer patients, treated for chemotherapy (Kawase et al. 2005). Since the expression of E-selectin and Mac-1 is regulated either directly or indirectly by NF-kB, studies provide in vivo evidence that tepoxalin is a potent inhibitor of NF-kB mediated events in animal models and this novel molecular mechanism clearly defines it as a new class of anti-inflammatory compounds. E-selectin transcription requires binding of transcription factors, NF-kB, ATF-2, and HMG-I(Y). HUVE cells treated with TNF-α showed E-selectin surface expression, which peaked at 4 h and then declined. However, ATF-2 binding was unchanged after stimulation with TNF-α. The termination of E-selectin expression is controlled at the level of transcription, with loss of protein-DNA interactions at only one of three NF-kB-binding sites in the E-selectin promoter (Boyle et al. 1999).

E-selectin is synthesized following X-ray exposure to doses as low as 0.5 Gy. X-ray-induced expression of E-selectin and ICAM-1 has been proposed to contribute to radiation injury in normal tissues. E-selectin expression does not require cytokine synthesis, but involves NF-kB activation (Hallahan et al. 1995). NFκB inhibition using NFκB inhibitors abrogates X-ray induced inflammatory mediators (Hallahan et al. 1998). Andrographolide, the principal component of medicinal plant Andrographis paniculata, has been shown to inhibit NF-kB activity and may attenuate allergic asthma via inhibition of the NF-kB signaling pathway. Andrographolide attenuated OVA-induced lung tissue eosinophilia and airway mucus production, mRNA expression of E-selectin, and inducible NOS in lung tissues. Findings implicate a potential therapeutic value of andrographolide in the treatment of asthma (Bao et al. 2009; Jiang et al. 2007).

Effects of TGF-β and IFN-γ on E-Selectin Expression: Transforming growth factor (TGF-β) has been shown to decrease the adhesiveness of endothelial cells for neutrophils, lymphocytes, and tumor cells. TGF-β inhibits the basal E-selectin expression and TNF-stimulated expression. While TGF-β had no effect on the expression of VCAM-1 and ICAM-1, the effect was additive with IL-4 in inhibiting the expression of E-selectin. Thus, perivascular TGF-β appears to act as an inhibitor of inflammatory responses involving neutrophils and a subset of lymphocytes (Gamble et al. 1993). IFN-γ down-regulates the induction by a viral mimetic, polyinosinic-polycytidylic acid [poly-(I:C)], of E-selectin. The inhibitory effect of IFN-γ on poly(I:C)-induced E-selectin was specific for dsRNA. Results indicated the role for IFN-γ in the regulation of E-selectin gene expression in response to dsRNA by a transcriptional mechanism independent of NF-kB, as well as by a minor decrease in message stability (Faruqi and DiCorleto 1997).

Retinoic Acid Inhibits the Expression of VCAM-1 but not E-Selectin: Several genes are regulated by tocopherols which can be categorized, based on their function. Genes that are related to inflammation, cell adhesion and platelet aggregation include E-selectin, ICAM-1, and others (Azzi et al. 2004). Retinoic acid and synthetic derivatives are known to exert anti-inflammatory effects in cutaneous diseases. Pretreatment with all-trans-retinoic acid (t-RA) specifically prevented TNFα-induced VCAM-1 expression, but not ICAM-1 and E-selectin induction (Gille et al. 1997). The TNFα-mediated activation of the human VCAM-1 promoter was also inhibited after t-RA treatment, while the ICAM-1 promoter activation was unaffected, indicating that the selective inhibition of CAM expression is regulated in part at the level of gene transcription. Furthermore, the transcriptional inhibition by t-RA appears to be mediated by its effects upon the activation of NF-kB-dependent complex formation. The specific inhibition of cytokine-mediated VCAM-1 gene expression in vitro provides a potential basis by which retinoids exert their biological effects at sites of inflammation in vivo (Gille et al. 1997). Radiation-induced expression of E-selectin was also blocked by t-RA, whereas 9-cis retinoic acid was ineffective. Application of statins and t-RA might have clinical impact in protecting against E-selectin-promoted metastasis, which might arise as an unwanted side effect from radiation treatment (Holler et al. 2009; Nubel et al. 2004).

Methylation of E-Selectin Promoter Gene Represses NF-kB Transactivation: The E-selectin promoter in cultured endothelial cells is under-methylated in comparison with non-expressing HeLa cells. Thus, methylation is likely to play a role in blocking E-selectin expression in non-endothelial cells (Smith et al. 1993). In intestine, MUC2 is the main mucin carrying s-Lex, which interacts with E-selectin. This interaction may contribute to the extravasation of tumor cells and thus to the metastases. In several colorectal carcinoma cell lines the methylation of the 5'-flanking region of MUC2 correlated with the suppression of the MUC2 gene. The increase in MUC2 expression after the inhibition of the methylation with 5-aza-2' deoxycytidine strongly supports the notion that the suppression of MUC2 gene is related to the methylation of the promoter (Riede et al. 1998).

44.10.3 Strategies to Combat Atherogenesis and Venous Thrombosis

The advances in the development of adhesion molecule blocking agents, as well as an insight into the potential of these molecules in cardiovascular therapy have been reviewed from time to time (Lutters et al. 2004). Prophylactic dosing of a recombinant P-selectin ligand decreases venous thrombosis in a dose-dependent fashion in both feline and nonhuman primate animal models. Additionally, treatment of 2-day iliac thrombi with a recombinant protein, P-selectin inhibitor, significantly improves vein reopening in nonhuman primates (Register 2009). It is interesting to note that P-selectin inhibition decreases thrombosis without adverse anticoagulation. Myers et al. (2005) evaluated an orally bioavailable inhibitor of P-selectin (PSI-697), which decreased thrombosis. Since, P-selectin is expressed on the surface of activated endothelial cells and platelets during thrombosis, targeting the plasminogen activator (PA) to P-selectin would enhance local thrombolysis and reduce bleeding risk. A urokinase (uPA)/anti-P-selectin antibody (HuSZ51) fusion protein is known to increase fibrinolysis in a hamster pulmonary embolism (Dong et al. 2004)

Aspirin reduces risks of myocardial infarction, stroke and cardiovascular death (Serebruany et al. 2004). The impact of cyclooxygenase (COX)-2 antagonist treatment on acute coronary risk is controversial. Prolonged COX-2 inhibition attenuates CRP and IL-6, does not modify P-selectin and MMP-9, and has no deleterious effect on endothelial function in stable patients with a history of recurrent acute coronary events and raised C-reactive protein (CRP) (Bogaty et al. 2004). Statins used in the control of hypercholesterolemia exert a protective effect on the endothelium reflected by a reduced level of circulating adhesion molecules. Statins exert a beneficial effects on endothelial function and atherosclerotic plaque, modulating oxidative stress and inflammation, with subsequent, well documented, primary and secondary prevention of CAD. Following statin treatment, sP-selectin, and ICAM-1 and highly sensitive CRP decreased compared to baseline levels. Other proteins (sVCAM-1, sE-selectin and platelet ECAM-1) did not show significant changes. In contrast to CRP, the reduction of sP-selectin concentrations correlated directly with the lowering of total cholesterol and inversely with the progression of CAD (Marschang et al. 2006)

44.10.4 Anti-inflammatory Drugs

While diclofenac is capable of inhibiting the expression of E-selectin, ICAM-1 and VCAM-1, the SJC13 is selective in inhibiting the expression of E-selectin and VCAM-1, but not ICAM-1 in endothelial cells. Nonsteroidal anti-inflammatory agents, such as sodium salicylate and aspirin, inhibit NF-κB-dependent gene activation. Salicylate blocked the TNF-α-induced increase in mRNA levels of adhesion molecules and gave a dose-dependent inhibition of TNF-α-induced surface expression of VCAM-1 and ICAM-1 with higher doses required to inhibit E-selectin expression. Ibuprofen appeared a potent inhibitor of IL-1α and TNF-α-induced surface expression of VCAM-1 and a less potent inhibitor of ICAM-1. Indomethacin, a nonsalicylate cyclooxygenase inhibitor, had no effect on surface expression of adhesion molecules, suggesting that the effects were not due to inhibition of cyclooxygenase (Pierce et al. 1996). Methimazole, used in treating autoimmune diseases, may also diminish pathological inflammation by suppressing E-selectin expression. The phenyl methimazole can also reduce cytokine-induced E-selectin expression and consequent leukocyte adhesion. Compound 10, which dramatically inhibits TNF-α-induced VCAM-1 mRNA and protein expression in human aortic endothelial cells, has a modest inhibitory effect on TNF-α induced E-selectin expression and has no effect on ICAM-1 expression (Dagia et al. 2004).

A thieno(2,3-d)pyrimidine, A-155918 inhibits the TNFα-induced expression of E-selectin, ICAM-1, or VCAM-1 on HEVCs (Stewart et al. 2001). Co-treatment of human endothelial cells with certain hydroxyflavones and flavanols blocks cytokine-induced ICAM-1, VCAM-1, and E-selectin expression on human endothelial cells. One of the potent flavones, apigenin, exhibited a dose- and time-dependent, reversible effect on adhesion protein expression as well as inhibiting adhesion protein upregulation at the transcriptional level (Gerritsen et al. 1996). Enalapril and losartan but not placebo induced a small but stable decrease of cardiovascular ICAM-1 and VCAM-1, while E-selectin and leukocyte expression of ICAM-1 remained unchanged. The lowering of plasma adhesion molecules may indicate an antiatherogenic effect of angiotensin II blockade in hypercholesterolemia (Graninger et al. 2004). Carbohydrates, Synthetic Oligopeptides and Steroids

Targeting interaction of selectins and appropriate carbohydrate ligand is a promising approach to treat chronic inflammation. β-1,3-glucan sulfate (PS3) has inhibitory activity toward L and P-selectins under static conditions (Alban et al. 2009). Access to synthetic carbohydrates is an urgent need for the development of carbohydrate-based drugs, vaccines, adjuvants as well as novel drug delivery systems. Besides traditional synthesis in solution, synthetic carbohydrates have been generated by chemoenzymatic methods as well as automated solid-phase synthesis. Synthetic oligosaccharides have proven to be useful for identifying ligands of carbohydrate-binding proteins such as C-type lectins and siglecs using glycan arrays. Furthermore, glyconanoparticles and glycodendrimers have been used for specific targeting of lectins of the immune system such as selectins, DC-SIGN, and CD22 (Lepenies et al. 2010).

Compounds that target both heparanase and selectins offer a promising approach for cancer therapy. Borsig et al. (2011) reported semisynthetic sulfated tri mannose C-C-linked dimers (STMCs) which are endowed with heparanase and selectin inhibitory activity. STMC hexasaccharide is an effective inhibitor of P-selectin in vivo. P-selectin-specific STMC attenuated metastasis in animal models, indicating that inhibition of tumor cell interaction with the vascular endothelium is critical for cancer dissemination. The small size, the stability of the C-C bond, and the chemically defined structure of STMCs make them superior to heparin derivatives and signify STMCs as valuable candidates for further evaluation.

Steroids down-regulate the expression of CAMs in endothelial cells stimulated by LPS in vitro. Low-dose hydrocortisone is a new treatment of patients with septic shock, a state that is characterized by an endothelial injury. Treatment with glucocorticoids differently affected the pattern of evolution of sCAMs, with sE-selectin being decreased and sICAM-1 being increased. Expression of sP-selectin and sVCAM-1 was not affected (Leone et al. 2004). Methotrexate (MTX) markedly reduces the expression of vascular E-selectin. A positive correlation between disease severity and the frequency of cutaneous lymphocyte-associated antigen (CLA)-positive T cells in the blood of untreated patients with psoriasis has been observed. It is suggested that MTX decreases the expression of CLA and E-selectin and that this may be a major mechanism for the therapeutic effect of MTX on psoriatic skin lesions (Sigmundsdottir et al. 2004).


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© Springer-Verlag Wien 2012

Authors and Affiliations

  1. 1.Department of BiophysicsPunjab UniversityChandigarhIndia

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