Advertisement

Sepsis pp 47-69 | Cite as

Overview of the Molecular Pathways and Mediators of Sepsis

  • Tristen T. Chun
  • Brittany A. Potz
  • Whitney A. Young
  • Alfred Ayala
Chapter
Part of the Respiratory Medicine book series (RM)

Abstract

Sepsis is a common clinical problem among the critically ill, and it is associated with high morbidity and mortality due to lack of effective therapeutic options. Sepsis results from dysregulation of immune responses to infection, characterized by mixed antagonistic response syndrome (MARS) in which both aspects of the pro-inflammatory and anti-inflammatory responses are believed to be present concomitantly. These immune responses are mediated by a number of immune cells, including monocytes, macrophages, dendritic cells, neutrophils, natural killer cells, γδ T cells, natural killer T cells, and T and B lymphocyte cells that comprise innate and adaptive immune system. In addition, a variety of molecules and pathways exist to help maintain a delicate balance between protection against invading pathogens and bystander host damage. This chapter will present a general overview of the molecular pathways and mediators involved in sepsis in an attempt to provide a framework for understanding potential targets for sepsis treatment.

Keywords

Sepsis Innate and adaptive immunity Systemic Inflammatory Response Syndrome (SIRS) Compensatory Anti-Inflammatory Response Syndrome (CARS) Mixed Antagonistic Response Syndrome (MARS) Pathogen-Associated Molecular Patterns (PAMPs) Danger-Associated Molecular Patterns (DAMPs) Pattern Recognition Receptors (PRRs) Toll-like Receptors (TLRs) Intracellular Patterns Recognition Systems (iPRSs) Cytokines and chemokines Immune resolution 

Abbreviations

APC

Antigen presenting cell

ATP

Adenosine triphosphate

CARS

Compensatory anti-inflammatory response syndrome

CAUTI

Catheter-associated urinary tract infections

CLABSI

Central line-associated blood stream infections

DAMP

Danger-associated molecular patterns

DC

Dendritic cell

DIC

Disseminated intravascular coagulation

DNA

Deoxyribonucleic acid

fMLP

Formyl-methionyl-leucyl-phenylalanine

HDL

High density lipoprotein

HMGB-1

High mobility group box-1

HSP

Heat shock protein

ICU

Intensive care units

IL

Interleukin

iNKT

Invariant natural killer T cell

iPRS

Intracellular patterns recognition systems

LBP

Lipopolysaccharide biding protein

LDL

Low density lipoprotein

LPS

Lipopolysaccharide

LTA

Lipoteichoic acid

MAC

Membrane attack complex

MAPK

Mitogen-activated protein kinase

MARS

Mixed antagonistic response syndrome

MCP

Monocyte chemotactic protein

MHC

Major histocompatibility complex

MIF

Migration inhibitory factor

MMP

Matrix metalloproteinase

MOF

Multiple organ failure

MSOF

Multisystem organ failure

NADPH

Nicotinamide adenine dinucleotide phosphate

NK

Natural killer cell

NKT

Natural killer T cell

NO

Nitric oxide

PAMP

Pathogen-associated molecular patterns

PAR

Protease-activated receptor

PG

Prostaglandin

PRR

Pattern recognition receptors

RA

Receptor antagonist

RIG-I

Retinoic-acid-inducible gene I

RNA

Ribonucleic acid

RNS

Reactive nitrogen species

ROS

Reactive oxygen species

S1P

Sphingosine-1 phosphate

sIL-R

Soluble interleukin receptor

SIRS

Systemic inflammatory response syndrome

TCR

T cell receptor

TGF

Transforming growth factor

TLR

Toll-like receptors

TNF

Tumor necrosis factor

VAP

Ventilator-associated pneumonia

VLDL

Very low density lipoprotein

References

  1. 1.
    Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29:1303–10.Google Scholar
  2. 2.
    Martin GS, Mannino DM, Eaton S. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;16:1546–54.CrossRefGoogle Scholar
  3. 3.
    Van Ruler O, Schultz MJ, Reitsma JB. Has mortality from sepsis improved and what to expect from new treatment modalities: review of current insights. Surg Infect (Larchmt). 2009;10:339–48.CrossRefGoogle Scholar
  4. 4.
    Cinel I, Opal SM. Molecular biology of inflammation and sepsis. Crit Care Med. 2009;37:291–304.CrossRefPubMedGoogle Scholar
  5. 5.
    Ward NS, Casserly B, Ayala A. The compensatory anti-inflammatory response syndrome (CARS) in critically ill patients. Clin Chest Med. 2008;29:617–25.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Burnet FM. The clonal selection theory of acquired immunity. Nashville, TN: Vanderbilt University Press; 1959.CrossRefGoogle Scholar
  7. 7.
    Matzinger P. The Danger Model: a renewed sense of self. Science. 2002;296:301–5.CrossRefPubMedGoogle Scholar
  8. 8.
    Hemmi H, Akira S. Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett. 2003;85(2):85–95.CrossRefPubMedGoogle Scholar
  9. 9.
    Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991.CrossRefPubMedGoogle Scholar
  10. 10.
    Matzinger P. Friendly and dangerous signals: is the tissue in control? Nat Immunol. 2007;8:11.CrossRefPubMedGoogle Scholar
  11. 11.
    Perl M, Chung CS, Garber M, Huang X, Ayala A. Contribution of anti-inflammatory/immune suppressive processes to the pathology of sepsis. Front Biosci. 2006;11:272–99.Google Scholar
  12. 12.
    Mai J, Wang H, Yang XF. Th 17 cells interplay with Foxp3+ Tregs in regulation of inflammation and autoimmunity. Front Biosci. 2010;15:986–1006.CrossRefGoogle Scholar
  13. 13.
    Marshall JC, Charbonney E, Gonzalez PD. The immune system in critical illness. Clin Chest Med. 2008;29:605–16.CrossRefPubMedGoogle Scholar
  14. 14.
    Von Knethen A, Tautenhahn A, Link H, Lindemann D, Brune B. Activation-induced depletion of protein kinase C alpha provokes desensitization of monocytes/macrophages in sepsis. J Immunol. 2005;174:4960–5.Google Scholar
  15. 15.
    Muñoz C, Carlet J, Fitting C, Misset B, Bleriot JP, Cavaillon JM. Dysregulation of in vitro cytokine production by monocytes during sepsis. J Clin Invest. 1991;88:1747–54.Google Scholar
  16. 16.
    Adib-Conquy M, Cavaillon JM. Compensatory anti-inflammatory response syndrome. Thromb Haemost. 2009;101:36–47.PubMedGoogle Scholar
  17. 17.
    Mbongue J, Nicholas D, Firek A, Langridge W. The role of dendritic cells in tissue-specific autoimmunity. J Immunol Res. 2014;857143 doi: 10.1155/2014/857143. Epub 2014 Apr 30
  18. 18.
    Serbina NV, Salazar-Mather TP, Biron CA, Kuziel WA, Pamer EG. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity. 2003;19:59–70.Google Scholar
  19. 19.
    Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–52.CrossRefPubMedGoogle Scholar
  20. 20.
    Barreira da Silva R, Münz C. Natural killer cell activation by dendritic cells: balancing inhibitory and activating signals. Cell Mol Life Sci. 2011;68:3505–18.CrossRefPubMedGoogle Scholar
  21. 21.
    Huang X, Venet F, Chung CS, Lomas-Neira J, Ayala A. Changes in dendritic cell function in the immune response to sepsis. Cell- & tissue-based therapy. Expert Opin Biol Ther. 2007;7:929–38.Google Scholar
  22. 22.
    Klebanoff SJ, Vadas MA, Harlan JM, Sparks LH, Gamble JR, Agosti JM, et al. Stimulation of neutrophils by tumor necrosis factor. J Immunol. 1986;136:4220–5.Google Scholar
  23. 23.
    Thakkar RK, Huang X, Lomas-Neira J, Heffernan D, Ayala A. Sepsis and the immune response. In: Essential immunology for surgeons. Oxford, UK: Oxford University Press; 2011. p. 303–42.Google Scholar
  24. 24.
    Jaeschke H, Smith CW. Mechanisms of neutrophil-induced parenchymal cell injury. J Leukoc Biol. 1997;61:647–53.PubMedGoogle Scholar
  25. 25.
    Luo HR, Loison F. Constitutive neutrophil apoptosis: mechanisms and regulation. Am J Hematol. 2007;83:288–95.CrossRefGoogle Scholar
  26. 26.
    Alves-Filho JC, de Freitas A, Spiller F, Souto FO, Cunha FQ. The role of neutrophils in severe sepsis. Shock 2008;Suppl 1;3–9.Google Scholar
  27. 27.
    Jimenez MF, Watson RW, Parodo J, Evans D, Foster D, Steinberg M, et al. Dysregulated expression of neutrophil apoptosis in the systemic inflammatory response syndrome. Arch Surg. 1997;132:1263–70.Google Scholar
  28. 28.
    Goldmann O, Chhatwal GS, Medina E. Contribution of natural killer cells to the pathogenesis of septic shock induced by Streptococcus pyogenes in mice. J Infect Dis. 2005;191:1280–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Zeerleder S, Hack CE, Caliezi C, van Mierlo G, Eerenberg-Belmer A, Wolbink A, et al. Activated cytotoxic T cells and NK cells in severe sepsis and septic shock and their role in multiple organ dysfunction. Clin Immunol. 2005;116:158–65.Google Scholar
  30. 30.
    Venet F, Chung CS, Monneret G, Huang X, Horner B, Garber M, et al. Regulatory T cell populations in sepsis and trauma. J Leukoc Biol. 2007;83:523–35.Google Scholar
  31. 31.
    Hotchkiss RS, Tinsley KW, Swanson PE, Schmieg Jr RE, Hui JJ, Chang KC, et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol. 2001;166:6952–63.Google Scholar
  32. 32.
    Ledere JA, Rodrick ML, Mannick JA. The effects of injury on the adaptive immune response. Shock. 1999;11:153–9.CrossRefGoogle Scholar
  33. 33.
    Ayala A, Deol ZK, Lehman DL, Herdon CD, Herdon CD, Chaudry IH. Polymicrobial sepsis but not low dose endotoxin infusion causes decreased splenocyte IL-2/IFN-gamma release while increasing IL-4/IL-10 production. J Surg Res. 1994;56:579–85.Google Scholar
  34. 34.
    Aziz M, Jacob A, Yang WL, Matsuda A, Wang P. Current trends in inflammatory and immunomodulatory mediators in sepsis. J Leukoc Biol. 2013;93:329–42.Google Scholar
  35. 35.
    Castellheim A, Brekke OL, Espevik T, Harboe M, Mollnes TE. Innate immune responses to danger signals in systemic inflammatory response syndrome and sepsis. Scand J Immunol. 2009;69:479–91.Google Scholar
  36. 36.
    Adib-Conquy M, Cavaillon JM. Stress molecules in sepsis and systemic inflammatory response syndrome. FEBS. 2007;581:3723–33.CrossRefGoogle Scholar
  37. 37.
    Spittler A, Razenberger M, Kupper H, et al. Relationship between interleukin-6 plasma concentration in patients with sepsis, monocyte phenotype, monocyte phagocytic properties, and cytokine production. Clin Infect Dis. 2000;31:1338–42.CrossRefPubMedGoogle Scholar
  38. 38.
    Osuchowski MF, Welch K, Siddiqui J, Kaul M, Hackl W, Boltz-Nitulescu G, et al. Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol. 2006;177:1967–74.Google Scholar
  39. 39.
    Cummings CJ, Martin TR, Frevert CW, Quan JM, Wong VA, Mongovin SM, et al. Expression and function of the chemokine receptors CXCR1 and CXCR2 in sepsis. J Immunol. 1999;162:2341.Google Scholar
  40. 40.
    Cooke JA, Wise WC, Butler RR, Reines HD, Rambo W, Halushka PV. The potential role of thromboxane and prostacyclin in endotoxic and septic shock. Am J Emerg Med. 1982;2:28–37.Google Scholar
  41. 41.
    Ayala A, Chung C, Grutkoski P, Song GY. Mechanisms of immune resolution. Crit Care Med. 2003;31(8):S558–71.Google Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Tristen T. Chun
    • 1
  • Brittany A. Potz
    • 2
  • Whitney A. Young
    • 3
  • Alfred Ayala
    • 4
  1. 1.Division of Surgical Research, Department of SurgeryRhode Island HospitalProvidenceUSA
  2. 2.Division of Surgical Research, Department of SurgeryRhode Island HospitalProvidenceUSA
  3. 3.Division of Surgical Research, Department of SurgeryRhode Island HospitalProvidenceUSA
  4. 4.Division of Surgical Research, Department of SurgeryRhode Island HospitalProvidenceUSA

Personalised recommendations