Abstract
The inflammatory response is highly integrated and involves regulatory elements released from the cells of the immune system, humoral factors, the endothelium, and endogenous danger signals. Once activated, the goal of the inflammatory response is to activate the cellular immune response to ward off penetrating pathogens and to initiate tissue repair mechanisms. The magnitude of the systemic response is proportional to the severity of the initial insult on the background of the genetic milieu of the individual. The inflammatory response is closely regulated and a counter anti-inflammatory response keeps it in check. When excessive or sustained, this immuno-inflammatory response gives way to prolonged immune suppression, leaving the individual susceptible to nosocomial infections and prolonged intensive care unit (ICU) stay. Only by understanding how the immune–inflammatory response becomes disordered can we devise strategies to limit the deleterious consequences.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
De Bosscher K et al (2003) The interplay between the glucocorticoid receptor and nuclear factor-κB or activator protein-1: molecular mechanisms for gene repression. Endocr Rev 24:488–522
Hierholzer C, Billiar TR (2001) Molecular mechanisms in the early phase of hemorrhagic shock. Langenbecks Arch Surg 386:302–308
Lenz A (2007) Systemic inflammation after trauma. Injury 38:1336–1345
Xiao W et al (2011) A genomic storm in critically injured humans. J Exp Med 208:2581–2590
Waltz P, Carchman EH, Young AC, Rao J, Rosengart MR, Kaczorowski D, Zuckerbraun BS (2011) Lipopolysaccaride induces autophagic signaling in macrophages via a TLR4, heme oxygenase-1 dependent pathway. Autophagy 7(3):315–320
Kaczorowski DJ, Mollen KP, Edmonds R, Billiar TR (2008) Early events in the recognition of danger signals after tissue injury. J Leukoc Biol 83(3):546–552
Mollen KP, Anand RJ, Tsung A, Prince JM, Levy RM, Billiar TR (2006) Emerging paradigm: toll-like receptor 4-sentinel for the detection of tissue damage. Shock 26(5):430–437
Eltzschig HK, Carmeliet P (2011) Hypoxia and Inflammation. N Engl J Med 364:656–665
Adams JM et al (2009) HIF-1: a key mediator in hypoxia. Acta Physiol Hung 96:19–28
Dehne N, Brune B (2009) HIF-1 in the inflammatory microenvironment. Exp Cell Res 315:1791–1797
Jassem W, Heaton ND (2004) The role of mitochondria in ischemia/reperfusion injury in organ transplantation. Kidney Int 66:514–517
Fink M (2002) Reactive oxygen species as mediators of organ dysfunction caused by sepsis, acute respiratory distress syndrome, or hemorrhagic shock: potential benefits of resuscitation with Ringer’s ethyl pyruvate solution. Curr Opin Clin Nutr Metab Care 5:167–174
Ahbub S et al (2011) Aging of the innate immune system: an update. Curr Immunol Rev 7:104–115
Maier R (2000) Pathogenesis of multiple organ dysfunction syndrome – endotoxin, inflammatory cells, and their mediators: cytokines and reactive oxygen species. Surg Infect 1:197–204
Fortin CF et al (2008) Aging and neutrophils: there is still much to do. Rejuvenation Res 11:873–882
Yousefi S, Mihalache C, Kozlowski E, Schmid I, Simon HU (2009) Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps. Cell Death Differ 16(11):1438–1444
Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD, Keys EM, Allen-Vercoe E, Devinney R, Doig CJ, Green FH, Kubes P (2007) Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 13:463–469
Maernkova VP et al (2006) CD11b+/GR-1+ myeloid suppressor cells cause T cell dysfunction after traumatic stress. J Immunol 176:2085–2094
Lord JM et al (2001) Mechanisms of ageing and development. Mech Ageing Dev 122:1521–1535
Mauri C, Bosma A (2012) Immune regulatory Function of B Cells. Annu Rev Immunol 30:221–241
Murphy TJ et al (2005) CD4+CD25+ regulatory T cells control innate immunity reactivity after injury. J Immunol 174:2957–2963
Wisnoski N et al (2007) The contribution of CD4+ CD25+ T-regulatory-cells to immune suppression in sepsis. Shock 27:251–257
Ni Choileain N et al (2006) Enhanced regulatory T cell activity is an element of the host response to injury. J Immunol 176:225–236
Barreira da Silva R, Münz C (2011) Natural killer cell activation by dendritic cells: balancing inhibitory and activating signals. Cell Mol Life Sci 68(21):3505–3518
Flodström M, Shi FD, Sarvetnick N, Ljunggren HG (2002) The natural killer cell – friend or foe in autoimmune disease? Scand J Immunol 55(5):432–441
Lünemann A, Lünemann JD, Münz C (2009) Regulatory NK-cell functions in inflammation and autoimmunity. Mol Med 15(9–10):352–358
Godfrey DI, Berzins SP (2007) Control points in NKT-cell development. Nat Rev Immunol 7(7):505–518
Pilones KA, Aryankalayil J, Demaria S (2012) Invariant NKT cells as novel targets for immunotherapy in solid tumors. Clin Dev Immunol 2012:720803
Chan WL, Pejnovic N, Liew TV, Lee CA, Groves R, Hamilton H (2003) NKT cell subsets in infection and inflammation. Immunol Lett 85(2):159–163
Faunce DE, Gamelli RL, Choudhry MA, Kovacs EJ (2003) A role for CD1d-restricted NKT cells in injury-associated T cell suppression. J Leukoc Biol 73(6):747–755
Tulley JM, Palmer JL, Gamelli RL, Faunce DE (2008) Prevention of injury-induced suppression of T-cell immunity by the CD1d/NKT cell-specific ligand alpha-galactosylceramide. Shock 29(2):269–277
Palmer JL, Tulley JM, Kovacs EJ, Gamelli RL, Taniguchi M, Faunce DE (2006) Injury-induced suppression of effector T cell immunity requires CD1d-positive APCs and CD1d-restricted NKT cells. J Immunol 177(1):92–99
Tinsley KW et al (2003) Sepsis induces apoptosis and profound depletion of splenic interdigitating and follicular dendritic cells. J Immunol 171:909–914
Hotchkiss RS et al (2002) Depletion of dendritic cells, but not macrophages, in patients with sepsis. J Immunol 168:2493–2500
Ding Y et al (2004) Polymicrobial sepsis induces divergent effects on splenic and peritoneal dendritic cell function in mice. Shock 22:137–144
Kawasaki T et al (2006) Trauma-hemorrhage induces depressed splenic dendritic cell functions in mice. J Imunol 177:4514–4520
Kawasaki T et al (2008) Trauma-hemorrhage inhibits splenic dendritic cell proinflammatory cytokine production via a mitogen-activated protein kinase process. Am J Physiol Cell Physiol 294:C754–C764
Seki E, Brenner DA (2008) Toll-like receptors and adaptor molecules in liver disease: update. Hepatology 48(1):322–335
Mayer AK, Muehmer M, Mages J, Gueinzius K, Hess C, Heeg K, Bals R, Lang R, Dalpke AH (2007) Differential recognition of TLR-dependent microbial ligands in human bronchial epithelial cells. J Immunol 178(5):3134–3142
Jilling T, Simon D, Lu J, Meng FJ, Li D, Schy R, Thomson RB, Soliman A, Arditi M, Caplan MS (2006) The roles of bacteria and TLR4 in rat and murine models of necrotizing enterocolitis. J Immunol 177(5):3273–3282
Sawa Y, Tsuruga E, Iwasawa K, Ishikawa H, Yoshida S (2008) Leukocyte adhesion molecule and chemokine production through lipoteichoic acid recognition by toll-like receptor 2 in cultured human lymphatic endothelium. Cell Tissue Res 333(2):237–252
Chakravarty S, Herkenham M (2005) Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines. J Neurosci 25(7):1788–1796
Buchholz BM, Chanthaphavong RS, Billiar TR, Bauer AJ (2012) Role of interleukin-6 in hemopoietic and non-hemopoietic synergy mediating TLR4-triggered late murine ileus and endotoxic shock. Neurogastroenterol Motil 24(7):658–669
Tsung A, Sahai R, Tanaka H, Nakao A, Fink MP, Lotze MT, Yang H, Li J, Tracey KJ, Geller DA, Billiar TR (2005) The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med 201:1135–1143
Ben-Ari Z, Avlas O, Fallach R, Schmilovitz-Weiss H, Chepurko Y, Pappo O, Hochhauser E (2012) Ischemia and reperfusion liver injury is reduced in the absence of Toll-like receptor 4. Cell Physiol Biochem 30(2):489–498
Hui W, Jinxiang Z, Heshui W, Zhuoya L, Qichang Z (2009) Bone marrow and non-bone marrow TLR4 regulates hepatic ischemia/reperfusion injury. Biochem Biophys Res Commun 389(2):328–332
Mollen KP, Levy RM, Prince JM, Hoffman RA, Scott MJ, Kaczorowski DJ, Vallabhaneni R, Vodovotz Y, Billiar TR (2008) Systemic inflammation and end organ damage following trauma involves functional TLR4 signaling in both bone marrow-derived cells and parenchymal cells. J Leukoc Biol 83(1):80–88
Tsung A, Klune JR, Zhang X, Jeyabalan G, Cao Z, Peng X, Stolz DB, Geller DA, Rosengart MR, Billiar TR (2007) HMGB1 release induced by liver ischemia involves Toll-like receptor 4 dependent reactive oxygen species production and calcium-mediated signaling. J Exp Med 204(12):2913–2923
Sawa Y, Ueki T, Hata M, Iwasawa K, Tsuruga E, Kojima H, Ishikawa H, Yoshida S (2008) LPS-induced IL-6, IL-8, VCAM-1, and ICAM-1 expression in human lymphatic endothelium. J Histochem Cytochem 56(2):97–109
Napoleone E, Di Santo A, Lorenzet R (2007) Monocytes upregulate endothelial cell expression of tissue factor: a role for cell-cell contact and cross-talk. Blood 89(2):541–549
Pober JS, Sessa WC (2007) Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 7(10):803–815
Norman MU, Lister KJ, Yang YH, Issekutz A, Hickey MJ (2005) TNF regulates leukocyte-endothelial cell interactions and microvascular dysfunction during immune complex-mediated inflammation. Br J Pharmacol 144(2):265–274
Varani J, Ward PA (1994) Mechanisms of endothelial cell injury in acute inflammation. Shock 2(5):311–319
Mellott JK, Nick HS, Waters MF, Billiar TR, Geller DA, Chesrown SE (2001) Cytokine-induced changes in chromatin structure and in vivo footprints in the inducible NOS promoter. Am J Physiol Lung Cell Mol Physiol 280(3):L390–L399
Beckman JS, Crow JP (1993) Pathological implications of nitric oxide, superoxide and peroxynitrite formation. Biochem Soc Trans 21(2):330–334
Hierholzer C, Harbrecht B, Menezes JM, Kane J, MacMicking J, Nathan CF, Peitzman AB, Billiar TR, Tweardy DJ (1998) Essential role of induced nitric oxide in the initiation of the inflammatory response after hemorrhagic shock. J Exp Med 187(6):917–928
Darwiche SS, Pfeifer R, Menzel C, Ruan X, Hoffman M, Cai C, Chanthaphavong RS, Loughran P, Pitt BR, Hoffman R, Pape HC, Billiar TR (2012) Inducible nitric oxide synthase contributes to immune dysfunction following trauma. Shock 38(5):499–507
Boehme MWJ et al (1996) Release of thrombomodulin from endothelial cells by concerted action of TNF-α and neutrophils: in vivo and in vitro studies. Immunology 87:134–140
Lentz SR et al (1991) Regulation of thrombomodulin by tumor necrosis factor-alpha: comparison of transcriptional and posttranscriptional mechanisms. Blood 77:542–550
Stouthard JM et al (1996) Interleukin-6 stimulates coagulation, not fibrinolysis, in humans. Thromb Haemost 76:738–742
Bevilacqua MP et al (1986) Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci USA 83:4533–4537
Davalos D, Akassoglou K (2012) Fibrinogen as a key regulator of inflammation in disease. Semin Immunopathol 34:43–62
Le Tylzo Y et al (1997) Hemorrhage increases cytokine expression in lung mononuclear cells in mice: involvement of catecholamines in nuclear factor-κB regulation and cytokine expression. Clin Invest 99:1516–1524
Kohm AP, Sanders VM (2001) Norepinephrine and beta 2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo. Pharmacol Rev 53(4):487–525
Liu Y, Yuan Y, Li Y, Zhang J, Xiao G, Vodovotz Y, Billiar TR, Wilson MA, Fan J (2009) Interacting neuroendocrine and innate and acquired immune pathways regulate neutrophil mobilization from bone marrow following hemorrhagic shock. J Immunol 182(1):572–580
Elhassan IO, Hannoush EJ, Sifri ZC, Jones E, Alzate WD, Rameshwar P, Livingston DH, Mohr AM (2011) Beta-blockade prevents hematopoietic progenitor cell suppression after hemorrhagic shock. Surg Infect (Larchmt) 12(4):273–278
Collins JL, Vodovotz Y, Yoneyama T, Hatakeyama K, Green AM, Billiar TR (2001) Catecholamines decrease nitric oxide production by cytokine-stimulated hepatocytes. Surgery 130(2):256–264
Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405(6785):458–462
Parrish WR, Rosas-Ballina M, Gallowitsch-Puerta M, Ochani M, Ochani K, Yang LH, Hudson L, Lin X, Patel N, Johnson SM, Chavan S, Goldstein RS, Czura CJ, Miller EJ, Al-Abed Y, Tracey KJ, Pavlov VA (2008) Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptor-mediated signaling. Mol Med 14:9–10
Pavlov VA, Ochani M, Gallowitsch-Puerta M, Ochani K, Huston JM, Czura CJ, Al-Abed Y, Tracey KJ (2006) Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc Natl Acad Sci USA 103(13):5219–5223
Lakhan SE, Kirchgessner A (2011) Anti-inflammatory effects of nicotine in obesity and ulcerative colitis. J Transl Med 9:129. doi:10.1186/1479-5876-9-129
Guslandi M (1999) Nicotine treatment for ulcerative colitis. Br J Clin Pharmacol 48(4):481–484
Setoguchi D, Yatsuki H, Sadahiro T, Nakamura M, Hirayama Y, Watanabe E, Tateishi Y, Oda S (2012) Effects of a peripheral cholinesterase inhibitor on cytokine production and autonomic nervous activity in a rat model of sepsis. Cytokine 57(2):238–244
Hofer S, Eisenbach C, Lukic IK, Schneider L, Bode K, Brueckmann M, Mautner S, Wente MN, Encke J, Werner J, Dalpke AH, Stremmel W, Nawroth PP, Martin E, Krammer PH, Bierhaus A, Weigand MA (2008) Pharmacologic cholinesterase inhibition improves survival in experimental sepsis. Crit Care Med 36(2):404–408
Namas R et al (2009) The acute response in trauma/hemorrhage and traumatic brain injury: current state and emerging prospects. Libyan J Med 4:97–103
Williams JP et al (1999) Intestinal reperfusion injury is mediated by IgM and complement. J Appl Physiol 86:938–942
Fleming SD et al (2002) Mice deficient in complement receptors 1 and 2 lack a tissue injury-inducing subset of the natural antibody repertoire. J Immunol 169:2126–2133
Thurman JM et al (2003) Lack of a functional alternative complement pathway ameliorates ischemic acute renal failure in mice. J Immunol 170:1517–1523
Kaczorowski DJ et al (2010) Pivotal advance: the pattern recognition receptor ligands lipopolysaccharide and polyinosine polycytidylic acid stimulate factor B synthesis by the macrophage through distinct but overlapping mechanisms. J Leukoc Biol 88:609–618
Kaczerowski DJ (2012) Mammalian DNA, is an endogenous danger signal that stimulates local synthesis and release of complement factor B. Mol Med 18:851–860
Cai C, Gill R, Eum HA, Cao Z, Loughran PA, Darwiche S, Edmonds RD, Menzel CL, Billiar TR (2010) Complement factor 3 deficiency attenuates hemorrhagic shock-related hepatic injury and systemic inflammatory response syndrome. Am J Physiol Regul Integr Comp Physiol 299(5):R1175–R1182
Moore FA, Moore EE (1995) Evolving concepts in the pathogenesis of postinjury multiple organ failure. Surg Clin North Am 75:257–277
De Maio A, Torres MB, Reeves RH (2005) Genetic determinants influencing the response to injury, inflammation, and sepsis. Shock 23(1):11–17
Schroder J, Kahlke V, Staubach KH, Zabel P, Stuber F (1998) Gender differences in human sepsis. Arch Surg 133(11):1200–1205
George RL, McGwin G Jr, Windham ST, Melton SM, Metzger J, Chaudry IH, Rue LW 3rd (2003) Age-related gender differential in outcome after blunt or penetrating trauma. Shock 19(1):28–32
Frink M, Pape HC, van Griensven M, Krettek C, Chaudry IH, Hildebrand F (2007) Influence of sex and age on mods and cytokines after multiple injuries. Shock 27(2):151–156
Hotchkiss RS et al (2005) Accelerated lymphocyte death in sepsis occurs by both the death receptor and mitochondrial pathways. J Immunol 174:5110–5118
Kasten KR et al (2010) T cells are potent early mediators of the host response to sepsis. Shock 34:327–336
Hotchkiss RS et al (1999) Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis. J Immunol 162:4148–4156
Kelly JL et al (1997) Anti-interleukin-10 antibody restores burn-induced defects in T-cell function. Surgery 122:146–152
Caterino JM et al (2010) Identification of an age cutoff for increased mortality in patients with elderly trauma. Am J Emerg Med 28:151–158
Tornetta P III et al (1999) Morbidity and mortality in elderly trauma patients. J Truama 46:702–706
Taylor MD et al (2002) Trauma in the elderly: intensive care unit use and outcome. J Trauma 53:407–414
Morris JA et al (1990) Mortality in trauma patients: the interaction between host factors and severity. J Trauma 30:1476–1482
Hollis S et al (2006) The effect of pre-existing medical conditions and age on mortality after injury. J Trauma 61:1255–1260
Tran DD et al (1990) Age, chronic disease, sepsis, organ system failure, and mortality in a medical intensive care unit. Crit Care Med 18:474–479
Bruunsgaard H, Pedersen BK (2003) Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am 23:15–39
Krabbe KS et al (2001) Ageing is associated with a prolonged fever response in human endotoxemia. Clin Diagn Lab Immunol 8:333–338
Chatta GS et al (1993) Hematopoietic progenitors and aging: alterations in granulocyte precursors and responsiveness to recombinant human G-CSF, GM-CSF and IL-3. J Gerontol 48:M207–M212
Fulop T et al (1997) Changes in apoptosis of human polymorphonuclear granulocytes with aging. Mech Ageing Dev 96:15–34
Hodes RJ (1999) Telomere length, aging, and somatic cell turnover. J Exp Med 190:153–156
Cakman I (1996) Dysregulation between TH1 and TH2 cell subpopulations in the elderly. Mech Ageing Dev 87:197–209
Rink L (1998) Altered cytokine production in the elderly. Mech Ageing Dev 102:199–209
Rus A et al (2010) Inducible NOS inhibitor 1400W reduces hypoxia/re-oxygenation injury in rat lung. Redox Rep 15:169–178
Kan WH et al (2008) Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation-induced hepatic injury. J Appl Physiol 105:1076–1082
Gennari R et al (1994) Effects of antimurine interleukin-6 on bacterial translocation during gut-derived sepsis. Arch Surg 129:1191–1197
Fontanilla CV et al (2000) Anti-interleukin-6 antibody treatment restores cell-mediated immune function in mice with acute ethanol exposures before burn trauma. Alcohol Clin Exp Res 24:1392–1399
O’Suilleabhain C et al (1996) Interleukin-12 treatment restores normal resistance to bacterial challenge after burn injury. Surgery 120:290–296
Colombo MP, Trinchieri G (2002) Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev 13:155–168
Howard M (1993) Interleukin 10 protects mice from lethal endotoxemia. J Exp Med 177:1205–1208
Van der Poll T et al (1995) Endogenous IL-10 protects mice from death during septic peritonitis. J Immunol 155:5397–5401
Greenberg MK et al (1995) Neutralization of IL-10 increases survival in a murine model of Klebsiella pneumonia. J Immunol 155:722–729
Lenz AM et al (2007) Endogenous IL-10 leads to impaired bacterial clearance and reduced survival in murine model of chronic peritonitis. Cytokine 40:207–215
Steinhauser ML (1999) IL-10 is a major mediator of sepsis-induced impairment in lung antibacterial host defense. J Immunol 162:392–399
Unsinger J et al (2010) IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol 184:3768–3779
Hotchkiss RS et al (1999) Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc Natl Acad Sci USA 96:14541–14546
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Zettel, K.R., Billiar, T.R. (2013). Disorder of Systemic Inflammation in Sepsis and Trauma: A Systems Perspective. In: Vodovotz, Y., An, G. (eds) Complex Systems and Computational Biology Approaches to Acute Inflammation. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8008-2_6
Download citation
DOI: https://doi.org/10.1007/978-1-4614-8008-2_6
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-8007-5
Online ISBN: 978-1-4614-8008-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)