Sepsis pp 5-15 | Cite as

Pathophysiological Aspects of Sepsis: An Overview

  • Yong-Ming Yao
  • Ying-Yi LuanEmail author
  • Qing-Hong Zhang
  • Zhi-Yong Sheng
Part of the Methods in Molecular Biology book series (MIMB, volume 1237)


Sepsis is defined as severe systemic inflammation in response to invading pathogens, or an uncontrolled hyperinflammatory response, as mediated by the release of various proinflammatory mediators. Although some patients may die rapidly from septic shock accompanied by an overwhelming systemic inflammatory response syndrome (SIRS) triggered by a highly virulent pathogen, most patients survive the initial phase of sepsis, showing multiple organ damage days or weeks later. These patients often demonstrate signs of immune suppression accompanied by enhanced inflammation. Sepsis is a result of a complex process; there is interaction of various pathways, such as inflammation, immunity, coagulation, as well as the neuroendocrine system. This treatise is an attempt to provide a summary of several key regulatory mechanisms and to present the currently recognized molecular pathways that are involved in the pathogenesis of sepsis.

Key words

Sepsis Inflammation Immunity Coagulation Neuroendocrine 



This work was supported, in part, by grants from the National Natural Science Foundation (81130035, 81372054, 81071545, 81272089, 81121004), the National Basic Research Program of China (2012CB518102), and the Medical Research Foundation of Chinese PLA (AWS11J008, BWS12J050).


  1. 1.
    Bone RC (1991) The pathogenesis of sepsis. Ann Intern Med 115:457–469PubMedCrossRefGoogle Scholar
  2. 2.
    Bone RC, Sprung CL, Sibbald WJ (1992) Definitions for sepsis and organ failure. Crit Care Med 20:724–726PubMedCrossRefGoogle Scholar
  3. 3.
    Parrillo JE, Parker MM, Natanson C et al (1990) Septic shock in humans: advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med 113:227–242PubMedCrossRefGoogle Scholar
  4. 4.
    Wang J, Hu Y, Deng WW et al (2009) Negative regulation of Toll-like receptor signaling pathway. Microbes Infect 11:321–327PubMedCrossRefGoogle Scholar
  5. 5.
    Chuang TH, Ulevitch RJ (2004) Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors. Nat Immunol 5:495–502PubMedCrossRefGoogle Scholar
  6. 6.
    Divanovic S, Trompette A, Atabani SF et al (2005) Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nat Immunol 6:571–578PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    An H, Hou J, Zhou J et al (2008) Phosphatase SHP-1 promotes TLR- and RIG-I-activated production of type I interferon by inhibiting the kinase IRAK1. Nat Immunol 9:542–550PubMedCrossRefGoogle Scholar
  8. 8.
    Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195PubMedCrossRefGoogle Scholar
  9. 9.
    Rouhiainen A, Kuja-Panula J, Wilkman E et al (2004) Regulation of monocyte migration by amphoterin (HMGB1). Blood 104:1174–1182PubMedCrossRefGoogle Scholar
  10. 10.
    Zhu XM, Yao YM, Liang HP et al (2009) The effects of high mobility group box-1 protein on splenic dendritic cell maturation in rats. J Interferon Cytokine Res 29:677–686PubMedCrossRefGoogle Scholar
  11. 11.
    Huang LF, Yao YM, Zhang LT et al (2009) The effect of mobility group box-1 protein on activity of regulatory cells after thermal injury in rats. Shock 31:322–329PubMedCrossRefGoogle Scholar
  12. 12.
    Souza HP, Lima-Salgado T, da Cruz Neto LM (2010) Toll-like receptors in sepsis: a tale still being told. Endocr Metab Immune Disord Drug Targets 10:285–291PubMedCrossRefGoogle Scholar
  13. 13.
    Chang KC, Unsinger J, Davis CG et al (2007) Multiple triggers of cell death in sepsis: death receptor and mitochondrial-mediated apoptosis. FASEB J 21:708–719PubMedCrossRefGoogle Scholar
  14. 14.
    Prakash PS, Caldwell CC, Lentsch AB et al (2012) Human microparticles generated during sepsis in patients with critical illness are neutrophil-derived and modulate the immune response. J Trauma Acute Care Surg 73:401–406PubMedCrossRefGoogle Scholar
  15. 15.
    Andriantsitohaina R, Gaceb A, Vergori L et al (2012) Microparticles as regulators of cardiovascular inflammation. Trends Cardiovasc Med 22:88–92PubMedCrossRefGoogle Scholar
  16. 16.
    Ma T, Han L, Gao Y et al (2008) The endoplasmic reticulum stress-mediated apoptosis signal pathway is involved in sepsis-induced abnormal lymphocyte apoptosis. Eur Surg Res 41:219–225PubMedCrossRefGoogle Scholar
  17. 17.
    Weber SU, Schewe JC, Lehmann LE et al (2008) Induction of Bim and Bid gene expression during accelerated apoptosis in severe sepsis. Crit Care 12:R128PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Schwulst SJ, Muenzer JT, Peck-Palmer OM et al (2008) Bim siRNA decreases lymphocyte apoptosis and improves survival in sepsis. Shock 30:127–134PubMedGoogle Scholar
  19. 19.
    Jimbo A, Fujita E, Kouroku Y et al (2003) ER stress induces caspase-8 activation, stimulating cytochrome c release and caspase-9 activation. Exp Cell Res 283:156–166PubMedCrossRefGoogle Scholar
  20. 20.
    Oakes SA, Lin SS, Bassik MC (2006) The control of endoplasmic reticulum initiated apoptosis by the BCL-2 family of proteins. Curr Mol Med 6:99–109PubMedCrossRefGoogle Scholar
  21. 21.
    Kadowaki N, Ho S, Antonenko S et al (2001) Subsets of human dendritic cell precursors express different Toll-like receptors and respond to different microbial antigens. J Exp Med 194:863–869PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Pène F, Courtine E, Ouaaz F et al (2009) Toll-like receptors 2 and 4 contribute to sepsis-induced depletion of spleen dendritic cells. Infect Immun 77:5651–5658PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Akdis M, Akdis CA (2007) Mechanisms of allergen-specific immunotherapy. J Allergy Clin Immunol 119:780–791PubMedCrossRefGoogle Scholar
  24. 24.
    Kamimura D, Bevan MJ (2008) Endoplasmic reticulum stress regulator XBP-1 contributes to effector CD8+ T cell differentiation during acute infection. J Immunol 181:5433–5441PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Zhu XM, Yao FH, Yao YM et al (2012) Endoplasmic reticulum stress and its regulator XBP-1 contributes to dendritic cell maturation and activation induced by high mobility group box-1 protein. Int J Biochem Cell Biol 44:1097–1105PubMedCrossRefGoogle Scholar
  26. 26.
    Fujita S, Seino K, Sato K et al (2006) Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response. Blood 107:3656–3664PubMedCrossRefGoogle Scholar
  27. 27.
    Levi M, van der Poll T (2010) Inflammation and coagulation. Crit Care Med 38:S26–S34PubMedCrossRefGoogle Scholar
  28. 28.
    Levi M (2010) The coagulant response in sepsis and inflammation. Hamostaseologie 30(10–12):14–16Google Scholar
  29. 29.
    Weismüller K, Bauer M, Hofer S et al (2010) The neuroendocrine axis and the pathophysiology of sepsis. Anasthesiol Intensivmed Notfallmed Schmerzther 45:574–578PubMedCrossRefGoogle Scholar
  30. 30.
    Berczi I, Quintanar-Stephano A, Kovacs K (2009) Neuroimmune regulation in immunocompetence, acute illness, and healing. Ann N Y Acad Sci 1153:220–239PubMedCrossRefGoogle Scholar
  31. 31.
    Sharshar T, Hopkinson NS, Orlikowski D et al (2005) Science review: the brain in sepsis—culprit and victim. Crit Care 9:37–44PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Lang CH, Nystrom G, Frost RA (2008) Beta-adrenergic blockade exacerbates sepsis-induced changes in tumor necrosis factor alpha and interleukin-6 in skeletal muscle and is associated with impaired translation initiation. J Trauma 64:477–486PubMedCrossRefGoogle Scholar
  33. 33.
    Wang H, Yu M, Ochani M et al (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421:384–388PubMedCrossRefGoogle Scholar
  34. 34.
    Ameri P, Ferone D (2012) Diffuse endocrine system, neuroendocrine tumors and immunity: What’s new? Neuroendocrinology 95:267–276PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Yong-Ming Yao
    • 1
  • Ying-Yi Luan
    • 1
    Email author
  • Qing-Hong Zhang
    • 1
  • Zhi-Yong Sheng
    • 1
  1. 1.Department of Microbiology and ImmunologyBurns Institute, First Hospital Affiliated to the Chinese PLA General HospitalBeijingPeople’s Republic of China

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