Skip to main content
SpringerLink
Log in

Overview of the Molecular Pathways and Mediators of Sepsis

  • Chapter
  • First Online:
Sepsis

Part of the book series: Respiratory Medicine ((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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 69.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 119.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

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. 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. 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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  4. Cinel I, Opal SM. Molecular biology of inflammation and sepsis. Crit Care Med. 2009;37:291–304.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Burnet FM. The clonal selection theory of acquired immunity. Nashville, TN: Vanderbilt University Press; 1959.

    Book  Google Scholar 

  7. Matzinger P. The Danger Model: a renewed sense of self. Science. 2002;296:301–5.

    Article  CAS  PubMed  Google Scholar 

  8. Hemmi H, Akira S. Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett. 2003;85(2):85–95.

    Article  PubMed  Google Scholar 

  9. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol. 1994;12:991.

    Article  CAS  PubMed  Google Scholar 

  10. Matzinger P. Friendly and dangerous signals: is the tissue in control? Nat Immunol. 2007;8:11.

    Article  CAS  PubMed  Google Scholar 

  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. 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.

    Article  CAS  Google Scholar 

  13. Marshall JC, Charbonney E, Gonzalez PD. The immune system in critical illness. Clin Chest Med. 2008;29:605–16.

    Article  PubMed  Google Scholar 

  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. 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. Adib-Conquy M, Cavaillon JM. Compensatory anti-inflammatory response syndrome. Thromb Haemost. 2009;101:36–47.

    CAS  PubMed  Google Scholar 

  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. 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. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–52.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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. 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. Jaeschke H, Smith CW. Mechanisms of neutrophil-induced parenchymal cell injury. J Leukoc Biol. 1997;61:647–53.

    CAS  PubMed  Google Scholar 

  25. Luo HR, Loison F. Constitutive neutrophil apoptosis: mechanisms and regulation. Am J Hematol. 2007;83:288–95.

    Article  Google Scholar 

  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. 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. 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.

    Article  PubMed  Google Scholar 

  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. 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. 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. Ledere JA, Rodrick ML, Mannick JA. The effects of injury on the adaptive immune response. Shock. 1999;11:153–9.

    Article  Google Scholar 

  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. 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. 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. Adib-Conquy M, Cavaillon JM. Stress molecules in sepsis and systemic inflammatory response syndrome. FEBS. 2007;581:3723–33.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. 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. 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. Ayala A, Chung C, Grutkoski P, Song GY. Mechanisms of immune resolution. Crit Care Med. 2003;31(8):S558–71.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Surgical Research, Department of Surgery, Rhode Island Hospital, 593 Eddy Street Aldrich 226, Providence, RI, 02903, USA

    Tristen T. Chun MD

  2. Division of Surgical Research, Department of Surgery, Rhode Island Hospital, 2 Dudley Street MOC 360, Providence, RI, 02905, USA

    Brittany A. Potz MD

  3. Division of Surgical Research, Department of Surgery, Rhode Island Hospital, 593 Eddy Street Aldrich 242, Providence, RI, 02903, USA

    Whitney A. Young MD

  4. Division of Surgical Research, Department of Surgery, Rhode Island Hospital, 593 Eddy Street Aldrich 227, Providence, RI, 02903, USA

    Alfred Ayala PhD

Authors
  1. Tristen T. Chun MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brittany A. Potz MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Whitney A. Young MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alfred Ayala PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alfred Ayala PhD .

Editor information

Editors and Affiliations

  1. Division of Pulmonary Critical Care, and Sleep Medicine, Alpert/Brown Medical School, Providence, Rhode Island, USA

    Nicholas S. Ward

  2. Division of Pulmonary Critical Care, and Sleep Medicine, Alpert/Brown Medical School, Providence, Rhode Island, USA

    Mitchell M. Levy

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Cite this chapter

Chun, T.T., Potz, B.A., Young, W.A., Ayala, A. (2017). Overview of the Molecular Pathways and Mediators of Sepsis. In: Ward, N., Levy, M. (eds) Sepsis. Respiratory Medicine. Humana Press, Cham. https://doi.org/10.1007/978-3-319-48470-9_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-48470-9_4

  • Published:

  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-48468-6

  • Online ISBN: 978-3-319-48470-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation