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. 2007 Sep 11;9(5):358–365. doi: 10.1007/s11908-007-0056-6

Sepsis mediators

François Philippart, Jean-Marc Cavaillon 1,✉
PMCID: PMC7102023  PMID: 17880845

Abstract

During sepsis, the plasma levels of numerous inflammatory markers are enhanced. Some of these markers are the mediators responsible for the syndromes observed during sepsis as well as for organ dysfunction and eventually death. Their role has been demonstrated in experimental models that employed either transgenic and gene-targeted animals or the use of neutralizing agents. Accordingly, anaphylatoxins generated after complement system activation, factors of coagulation and fibrinolysis, proinflammatory cytokines, chemokines, proteases, lipid mediators, nitric oxide, and cell markers of stress (eg, high mobility group box-1) have been shown to contribute to the deleterious events observed during sepsis. On the other hand, the counterregulation of the inflammatory process, which involves mediators such as anti-inflammatory cytokines and some neuromediators, can jeopardize the immune status of the host and render the patients more sensitive to nosocomial infections.

Keywords: Septic Shock, Severe Sepsis, Migration Inhibitory Factor, Factor Xiii, Macrophage Migration Inhibitory Factor

References and Recommended Reading

  • 1.Haeffner-Cavaillon N., Cavaillon J.M., Laude M., Kazatchkine M.D. C3a(C3adesArg) induces production and release of interleukin 1 by cultured human monocytes. J Immunol. 1987;139:794–799. [PubMed] [Google Scholar]
  • 2.Cavaillon J.M., Fitting C., Haeffner-Cavaillon N. Recombinant C5a enhances interleukin 1 and tumor necrosis factor release by lipopolysaccharide-stimulated monocytes and macrophages. Eur J Immunol. 1990;20:253–257. doi: 10.1002/eji.1830200204. [DOI] [PubMed] [Google Scholar]
  • 3.Niederbichler A.D., Hoesel L.M., Westfall M.V., et al. An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction. J Exp Med. 2006;203:53–61. doi: 10.1084/jem.20051207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Ward P.A. The dark side of C5a in sepsis. Nature Rev Immunol. 2004;4:133–142. doi: 10.1038/nri1269. [DOI] [PubMed] [Google Scholar]
  • 5.Liu D., Zhang D., Scafidi J., et al. C1 inhibitor prevents Gram-negative bacterial lipopolysaccharide-induced vascular permeability. Blood. 2005;105:2350–2355. doi: 10.1182/blood-2004-05-1963. [DOI] [PubMed] [Google Scholar]
  • 6.Liu D., Cai S., Gu X., et al. C1 inhibitor prevents endotoxin shock via a direct interaction with lipopolysaccharide. J Immunol. 2003;171:2594–2601. doi: 10.4049/jimmunol.171.5.2594. [DOI] [PubMed] [Google Scholar]
  • 7.Osterud B., Flaegstad T. Increased tissue thromboplastin activity in monocytes of patients with meningococcal infection: related to an unfavourable prognosis. Thromb Haemost. 1983;49:5–7. [PubMed] [Google Scholar]
  • 8.Zeerleder S., Schroeder V., Lammle B., et al. Factor XIII in severe sepsis and septic shock. Thromb Res. 2007;119:311–318. doi: 10.1016/j.thromres.2006.02.003. [DOI] [PubMed] [Google Scholar]
  • 9.Bernard G.R., Vincent J.L., Laterre P.F., et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699–709. doi: 10.1056/NEJM200103083441001. [DOI] [PubMed] [Google Scholar]
  • 10.Yan S.B., Helterbrand J.D., Hartman D.L., et al. Low levels of protein C are associated with poor outcome in severe sepsis. Chest. 2001;120:915–922. doi: 10.1378/chest.120.3.915. [DOI] [PubMed] [Google Scholar]
  • 11.Verbon A., Meijers J.C., Spek C.A., et al. Effects of IC14, an anti-CD14 antibody, on coagulation and fibrinolysis during low-grade endotoxemia in humans. J Infect Dis. 2003;187:55–61. doi: 10.1086/346043. [DOI] [PubMed] [Google Scholar]
  • 12.Madoiwa S., Nunomiya S., Ono T., et al. Plasminogen activator inhibitor 1 promotes a poor prognosis in sepsis-induced disseminated intravascular coagulation. Int J Hematol. 2006;84:398–405. doi: 10.1532/IJH97.05190. [DOI] [PubMed] [Google Scholar]
  • 13.Renckens R., Roelofs J.J., Bonta P.I., et al. Plasminogen activator inhibitor type 1 is protective during severe Gramnegative pneumonia. Blood. 2007;109:1593–1601. doi: 10.1182/blood-2006-05-025197. [DOI] [PubMed] [Google Scholar]
  • 14.Cavaillon J.M., Adib-Conquy M., Fitting C., et al. Cytokine cascade in sepsis. Scand J Infect Dis. 2003;35:535–544. doi: 10.1080/00365540310015935. [DOI] [PubMed] [Google Scholar]
  • 15.Cavaillon J.M., Munoz C., Fitting C., et al. Circulating cytokines: the tip of the iceberg? Circ Shock. 1992;38:145–152. [PubMed] [Google Scholar]
  • 16.Sappington P.L., Yang R., Yang H., et al. HMGB1 increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice. Gastroenterology. 2002;123:790–802. doi: 10.1053/gast.2002.35391. [DOI] [PubMed] [Google Scholar]
  • 17.Amiot F., Fitting C., Tracey K.J., et al. Lipopolysaccharideinduced cytokine cascade and lethality in LT alpha/TNF alpha-deficient mice. Mol Med. 1997;3:864–875. [PMC free article] [PubMed] [Google Scholar]
  • 18.Vermont C.L., Hazelzet J.A., de Kleijn E.D., et al. CC and CXC chemokine levels in children with meningococcal sepsis accurately predict mortality and disease severity. Crit Care. 2006;10:R33. doi: 10.1186/cc4836. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Moreno S.E., Alves-Filho J.C., Alfaya T.M., et al. IL-12, but not IL-18, is critical to neutrophil activation and resistance to polymicrobial sepsis induced by cecal ligation and puncture. J Immunol. 2006;177:3218–3224. doi: 10.4049/jimmunol.177.5.3218. [DOI] [PubMed] [Google Scholar]
  • 20.Netea M.G., Fantuzzi G., Kullberg B.J., et al. Neutralization of IL-18 reduces neutrophil tissue accumulation and protects mice against lethal Escherichia coli and Salmonella typhimurium endotoxemia. J Immunol. 2000;164:2644–2649. doi: 10.4049/jimmunol.164.5.2644. [DOI] [PubMed] [Google Scholar]
  • 21.Hochholzer P., Lipford G.B., Wagner H., et al. Role of interleukin-18 (IL-18) during lethal shock: decreased lipopolysaccharide sensitivity but normal superantigen reaction in IL-18-deficient mice. Infect Immun. 2000;68:3502–3508. doi: 10.1128/IAI.68.6.3502-3508.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Qiu G., Gribbin E., Harrison K., et al. Inhibition of gamma interferon decreases bacterial load in peritonitis by accelerating peritoneal fibrin deposition and tissue repair. Infect Immun. 2003;71:2766–2774. doi: 10.1128/IAI.71.5.2766-2774.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Echtenacher B., Freudenberg M.A., Jack R.S., Mannel D.N. Differences in innate defense mechanisms in endotoxemia and polymicrobial septic peritonitis. Infect Immun. 2001;69:7271–7276. doi: 10.1128/IAI.69.12.7172-7276.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Yin K., Gribbin E., Wang H. Interferon-gamma inhibition attenuates lethality after cecal ligation and puncture in rats: implication of high mobility group box-1. Shock. 2005;24:396–401. doi: 10.1097/01.shk.0000175556.03300.c6. [DOI] [PubMed] [Google Scholar]
  • 25.Belladonna M.L., Vacca C., Volpi C., et al. IL-23 neutralization protects mice from Gram-negative endotoxic shock. Cytokine. 2006;34:161–169. doi: 10.1016/j.cyto.2006.04.011. [DOI] [PubMed] [Google Scholar]
  • 26.Wirtz S., Tubbe I., Galle P.R., et al. Protection from lethal septic peritonitis by neutralizing the biological function of interleukin 27. J Exp Med. 2006;203:1875–1881. doi: 10.1084/jem.20060471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Calandra T., Echtenacher B., Roy D.L., et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med. 2000;6:164–170. doi: 10.1038/72262. [DOI] [PubMed] [Google Scholar]
  • 28.Matsuda N., Nishihira J., Takahashi Y., et al. Role of macrophage migration inhibitory factor in acute lung injury in mice with acute pancreatitis complicated by endotoxemia. Am J Respir Cell Mol Biol. 2006;35:198–205. doi: 10.1165/rcmb.2005-0272OC. [DOI] [PubMed] [Google Scholar]
  • 29.Kaneider N.C., Agarwal A., Leger A.J., Kuliopulos A. Reversing systemic inflammatory response syndrome with chemokine receptor pepducins. Nat Med. 2005;11:661–665. doi: 10.1038/nm1245. [DOI] [PubMed] [Google Scholar]
  • 30.Yano K., Liaw P.C., Mullington J.M., et al. Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality. J Exp Med. 2006;203:1447–1458. doi: 10.1084/jem.20060375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Nakamura A., Mori Y., Hagiwara K., et al. Increased susceptibility to LPS-induced endotoxin shock in secretory leukoprotease inhibitor (SLPI)-deficient mice. J Exp Med. 2003;197:669–674. doi: 10.1084/jem.20021824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Renckens R., Roelofs J.J., Florquin S., et al. Matrix metalloproteinase-9 deficiency impairs host defense against abdominal sepsis. J Immunol. 2006;176:3735–3741. doi: 10.4049/jimmunol.176.6.3735. [DOI] [PubMed] [Google Scholar]
  • 33.Yassen K.A., Galley H.F., Webster N.R. Matrix metalloproteinase-9 concentrations in critically ill patients. Anaesthesia. 2001;56:729–732. doi: 10.1046/j.1365-2044.2001.02083.x. [DOI] [PubMed] [Google Scholar]
  • 34.Benjamim C.F., Canetti C., Cunha F.Q., et al. Opposing and hierarchical roles of leukotrienes in local innate immune versus vascular responses in a model of sepsis. J Immunol. 2005;174:1616–1620. doi: 10.4049/jimmunol.174.3.1616. [DOI] [PubMed] [Google Scholar]
  • 35.Ejima K., Layne M.D., Carvajal I.M., et al. Cyclooxygenase-2-deficient mice are resistant to endotoxin-induced inflammation and death. Faseb J. 2003;17:1325–1327. doi: 10.1096/fj.02-1078fje. [DOI] [PubMed] [Google Scholar]
  • 36.Gomes R.N., Bozza F.A., Amancio R.T., et al. Exogenous platelet-activating factor acetylhydrolase reduces mortality in mice with systemic inflammatory response syndrome and sepsis. Shock. 2006;26:41–49. doi: 10.1097/01.shk.0000209562.00070.1a. [DOI] [PubMed] [Google Scholar]
  • 37.Annane D., Sanquer S., Sebille V., et al. Compartmentalised inducible nitric-oxide synthase activity in septic shock. Lancet. 2000;355:1143–1148. doi: 10.1016/S0140-6736(00)02063-8. [DOI] [PubMed] [Google Scholar]
  • 38.Asakura H., Asamura R., Ontachi Y., et al. Selective inducible nitric oxide synthase inhibition attenuates organ dysfunction and elevated endothelin levels in LPS-induced DIC model rats. J Thromb Haemost. 2005;3:1050–1055. doi: 10.1111/j.1538-7836.2005.01248.x. [DOI] [PubMed] [Google Scholar]
  • 39.Benjamim C.F., Silva J.S., Fortes Z.B., et al. Inhibition of leukocyte rolling by nitric oxide during sepsis leads to reduced migration of active microbicidal neutrophils. Infect Immun. 2002;70:3602–3610. doi: 10.1128/IAI.70.7.3602-3610.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Matejovic M., Krouzecky A., Radej J., et al. Coagulation and endothelial dysfunction during longterm hyperdynamic porcine bacteremia—effects of selective inducible nitric oxide synthase inhibition. Thromb Haemost. 2007;97:304–309. [PubMed] [Google Scholar]
  • 41.Han X., Fink M.P., Uchiyama T., et al. Increased iNOS activity is essential for pulmonary epithelial tight junction dysfunction in endotoxemic mice. Am J Physiol Lung Cell Mol Physiol. 2004;286:L259–267. doi: 10.1152/ajplung.00187.2003. [DOI] [PubMed] [Google Scholar]
  • 42.Yang H., Ochani M., Li J., et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci U S A. 2004;101:296–301. doi: 10.1073/pnas.2434651100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Angus D.C., Yang L., Kong L., et al. Circulating high-mobility group box 1 (HMGB1) concentrations are elevated in both uncomplicated pneumonia and pneumonia with severe sepsis. Crit Care Med. 2007;35:1061–1067. doi: 10.1097/01.CCM.0000259534.68873.2A. [DOI] [PubMed] [Google Scholar]
  • 44.Tsung A., Sahai R., Tanaka H., et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med. 2005;201:1135–1143. doi: 10.1084/jem.20042614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Qin S., Wang H., Yuan R., et al. Role of HMGB1 in apoptosis-mediated sepsis lethality. J Exp Med. 2006;203:1637–1642. doi: 10.1084/jem.20052203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Bouchon A., Facchetti F., Weigand M.A., Colonna M. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature. 2001;410:1103–1107. doi: 10.1038/35074114. [DOI] [PubMed] [Google Scholar]
  • 47.Adib-Conquy M, Goulenok M, Laurent C, et al.: Enhanced plasma levels of soluble triggering expressed on myeloid cells-1 and procalcitonin after cardiac surgery and cardiac arrest in the absence of infection. Shock 2007, in press. [DOI] [PubMed]
  • 48.Moestrup S.K., Moller H.J. CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response. Ann Med. 2004;36:347–354. doi: 10.1080/07853890410033171. [DOI] [PubMed] [Google Scholar]
  • 49.Imai T., Fujita T., Yamazaki Y. Beneficial effects of apolipoprotein A-I on endotoxemia. Surg Today. 2003;33:684–687. doi: 10.1007/s00595-003-2585-4. [DOI] [PubMed] [Google Scholar]
  • 50.Jacque B., Stephan K., Smirnova I., et al. Mice expressing high levels of soluble CD14 retain LPS in the circulation and are resistant to LPS-induced lethality. Eur J Immunol. 2006;36:3007–3016. doi: 10.1002/eji.200636038. [DOI] [PubMed] [Google Scholar]
  • 51.Munford R.S., Pugin J. Normal responses to injury prevent systemic inflammation and can be immunosuppressive. Am J Respir Crit Care Med. 2001;163:316–321. doi: 10.1164/ajrccm.163.2.2007102. [DOI] [PubMed] [Google Scholar]
  • 52.Pathan N., Hemingway C.A., Alizadeh A.A., et al. Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock. Lancet. 2004;363:203–209. doi: 10.1016/S0140-6736(03)15326-3. [DOI] [PubMed] [Google Scholar]
  • 53.Witzenbichler B., Westermann D., Knueppel S., et al. Protective role of angiopoietin-1 in endotoxic shock. Circulation. 2005;111:97–105. doi: 10.1161/01.CIR.0000151287.08202.8E. [DOI] [PubMed] [Google Scholar]
  • 54.Orfanos S.E., Kotanidou A., Glynos C., et al. Angiopoietin-2 is increased in severe sepsis: correlation with inflammatory mediators. Crit Care Med. 2007;35:199–206. doi: 10.1097/01.CCM.0000251640.77679.D7. [DOI] [PubMed] [Google Scholar]
  • 55.Imai Y., Kuba K., Rao S., et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436:112–116. doi: 10.1038/nature03712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Faggioni R., Fantuzzi G., Gabay C., et al. Leptin deficiency enhances sensitivity to endotoxin-induced lethality. Am J Physiol. 1999;276:R136–142. doi: 10.1152/ajpregu.1999.276.1.R136. [DOI] [PubMed] [Google Scholar]
  • 57.Puneet P., Hegde A., Ng S.W., et al. Preprotachykinin-A gene products are key mediators of lung injury in polymicrobial sepsis. J Immunol. 2006;176:3813–3820. doi: 10.4049/jimmunol.176.6.3813. [DOI] [PubMed] [Google Scholar]
  • 58.Deng J., Muthu K., Gamelli R., et al. Adrenergic modulation of splenic macrophage cytokine release in polymicrobial sepsis. Am J Physiol Cell Physiol. 2004;287:C730–736. doi: 10.1152/ajpcell.00562.2003. [DOI] [PubMed] [Google Scholar]
  • 59.Wong L.Y., Cheung B.M., Li Y.Y., Tang F. Adrenomedullin is both proinflammatory and anti-inflammatory: its effects on gene expression and secretion of cytokines and macrophage migration inhibitory factor in NR8383 macrophage cell line. Endocrinology. 2005;146:1321–1327. doi: 10.1210/en.2004-1080. [DOI] [PubMed] [Google Scholar]
  • 60.Borovikova L.V., Ivanova S., Zhang M., et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–462. doi: 10.1038/35013070. [DOI] [PubMed] [Google Scholar]
  • 61.Pavlov V.A., Ochani M., Gallowitsch-Puerta M., et al. Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc Natl Acad Sci U S A. 2006;103:5219–5223. doi: 10.1073/pnas.0600506103. [DOI] [PMC free article] [PubMed] [Google Scholar]

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