Skip to main content
SpringerLink
Log in

Pathophysiologische Grundlagen der chirurgisch-bedingten Sepsis

Pathophysiological basis of surgery-linked sepsis

  • Leitthema
  • Published:
Der Chirurg Aims and scope Submit manuscript

Zusammenfassung

Infektionen und Traumata, einschließlich operativer Eingriffe, rufen eine systemische inflammatorische Antwort des Organismus hervor. Diese Immunantwort muss fein abgestimmt und genau geregelt werden, da sowohl eine zu geringe als auch eine überschießende Reaktion zu einer erhöhten Mortalität führen kann. Aktivierte Rezeptoren des angeborenen Immunsystems („pattern-recognition receptors“, PRRs) erkennen sog. „damage-associated molecular patterns“ (DAMPs), d. h. spezifische Strukturmotive exogener Pathogene („pathogen-associated molecular patterns“, PAMPs) und endogener zelldebrisassoziierter Pathogene (Alarmine), und können dabei zu einer überschießenden Immunantwort führen. Letztere ist durch ein komplexes Wechselspiel von Zytokinen und Chemokinen, amplifizierende Interaktionen der Gerinnungs-, Komplement- und Entzündungskaskade sowie die Kommunikation von Zellen des angeborenen und erworbenen Immunsystems charakterisiert. Das pathophysiologische Hauptereignis bei der Sepsis ist der Übergang vom anfänglichen hyperentzündlichen Zustand in die Immunparalyse und die zelluläre Anergie mit einer hohen Suszeptibilität der Patienten für sekundäre Infektionen und protrahierte Organschäden. Eine mit dem chirurgischen Trauma per se verbundene Immundysfunktion erhöht das Risiko einer Sepsis mit einem aggravierten Verlauf. Die Immunosuppression wird durch die massive Apoptose von Lymphozyten und dendritischen Zellen, die reduzierte HLA-DR-Expression und das verstärkte Vorliegen von negativ kostimulatorischen Molekülen vermittelt. Neben der Zunahme der T-Zellzahl kommt es zur Verschiebung vom entzündlichen Th1-Phänotyp zu einem antiinflammatorischen Th2-Phänotyp mit der Produktion von Interleukin-10. Weitere Schlüsselmediatoren der Sepsis sind HMGB1, MIF und der Komplementfaktor C5a. Durch die Identifizierung zentraler pathomechanistischer Ereignisse, wie z. B. die Immundysbalance, die Neuroimmunmodulation über den cholinergen antiinflammatorischen Reflex und die komplexe Interaktion von Gerinnung, Entzündung und Komplementkaskade besteht jetzt die Möglichkeit, neuartige Therapeutika zu entwickeln, welche eher die Modulation und weniger die Inhibition der Wirtsreaktion zum Ziel haben.

Abstract

Infection or injury, including surgical procedures, induces an inflammatory response of the host organism. This immune response must be finely tuned and precisely regulated, because deficiencies or excesses of the inflammatory response cause morbidity and shorten the lifespan. Activated receptors of the innate immune system (pattern recognition receptors, PRRs), which recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) including injured tissue-associated intracellular proteins (alarmins), lead to an exaggerated immune response. This is characterized by a complex interplay of cytokines, chemokines, complement and coagulation factors as well as inflammatory and immune regulatory cells. There is increasing recognition that the major pathophysiologic event in sepsis is the progression from the initial hyperinflammatory state to an immunosuppressive state in which the host is unable to eradicate invading pathogens and particularly prone to develop secondary nosocomial infections and organ damage. Surgical trauma-associated immune dysfunction per se predisposes the host to surgery-related sepsis. Immune suppression is mediated by massive apoptosis-induced depletion of lymphocytes and dendritic cells, decreased expression of the cell surface antigen complex HLA-DR and increased expression of negative costimulatory molecules. Besides increased numbers of regulatory T cells there is a shift from a phenotype of inflammatory Th1 cells to an antiinflammatory phenotype of Th2 cells characterized by the production of interleukin-10. Key mediators of sepsis are HMGB1, MIF and complement factor C5a. With the identification of central pathomechanistic events, e.g. amplification of the coagulation, complement and inflammation cascades, immune dysbalance and neuroimmunomodulation via the cholinergic anti-inflammatory reflex, the opportunity now exists to apply these insights to the development of new and novel therapeutics aimed at modulating rather than inhibiting the systemic host response to infection.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3
Abb. 4
Abb. 5
Abb. 6
Abb. 7
Abb. 8

Abbreviations

AT-III:

Antithrombin-III

BTLA:

B- and T-lymphocyte attenuator

CARS:

compensatory anti-inflammatory response syndrome

COX-2:

Cyclooxygenase-2

CTLA-4:

cytotoxic T-lymphocyte-associated antigen-4

DAMPs:

damage-associated molecular patterns

DIG:

disseminierte intravaskuläre Gerinnung

HMGB1:

high mobility group B1 protein

IFN-γ:

Interferon-γ

IL-1β:

Interleukin-1β

iNOS:

induzierbare NO-Synthase

MAC:

membrane attacking complex

MBL:

mannose-binding lectin

MIF:

macrophage migration inhibiting factor

MyD 88:

myeloid differentiation factor 88

NFκB:

nuclear factor kappa B

NOD2:

nucleotide-binding oligomerization domain containing 2

PAF:

plättchenaktivierender Faktor

PAI-1:

Plasminogenaktivatorinhibitor-1

PAMPs:

pathogen-associated molecular patterns

PD-1:

programmed death-1

PD-L1:

PD-1 ligand

PIRO:

Prädisposition, Infektion, Reaktion und Organfunktion

PRRs:

pattern-recognition receptors

RAGE:

receptor for advanced glycation endproducts

SIRS:

systemic inflammatory response syndrome

SNPs:

single nucleotide polymorphisms

sRAGE:

soluble receptor for advanced glycation endproducts

sTREM-1:

soluble triggering receptor expressed on myeloid cells

TAFI:

thrombinaktivierbarer Fibrinolyseeinhibitor

TF:

tissue factor

TLRs:

Toll-like-Rezeptoren

TNF-α:

Tumornekrosefaktor-α

t-PA:

Gewebeplasminogenaktivator

vWF:

von Willebrand Faktor

Literatur

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

    PubMed  CAS  Google Scholar 

  2. Agnese DM, Calvano JE, Hahm SJ et al (2002) Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections. J Infect Dis 186:1522–1525

    Article  PubMed  CAS  Google Scholar 

  3. Bernik TR, Friedman SG, Ochani M et al (2002) Pharmacological stimulation of the cholinergic antiinflammatory pathway. J Exp Med 195:781–788

    Article  PubMed  CAS  Google Scholar 

  4. Bianchi ME (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81:1–5

    Article  PubMed  CAS  Google Scholar 

  5. Bick RL (1998) Disseminated intravascular coagulation: pathophysiological mechanisms and manifestations. Semin Thromb Hemost 24:3–18

    Article  PubMed  CAS  Google Scholar 

  6. Bone RC, Balk RA, Cerra FB et al (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101:1644–1655

    Article  PubMed  CAS  Google Scholar 

  7. Bopp C, Hofer S, Weitz J et al (2008) sRAGE is elevated in septic patients and associated with patients outcome. J Surg Res 147:79–83

    Article  PubMed  CAS  Google Scholar 

  8. Borovikova LV, Ivanova S, Zhang M et al (2000) Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458–462

    Article  PubMed  CAS  Google Scholar 

  9. Branagan G, Finnis D Wessex Colorectal Cancer Audit Working Group (2005) Prognosis after anastomotic leakage in colorectal surgery. Dis Colon Rectum 48:1021–1026

    Article  PubMed  Google Scholar 

  10. Calandra T, Roger T (2003) Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol 3:791–800

    Article  PubMed  CAS  Google Scholar 

  11. Calvano JE, Um JY, Agnese DM et al (2003) Influence of the TNF-alpha and TNF-beta polymorphisms upon infectious risk and outcome in surgical intensive care patients. Surg Infect (Larchmt) 4:163–169

    Google Scholar 

  12. Cavaillon JM, Adib-Conquy M (2007) Determining the degree of immunodysregulation in sepsis. Contrib Nephrol 156:101–111

    Article  PubMed  CAS  Google Scholar 

  13. Chandra V, Nelson H, Larson DR, Harrington JR (2004) Impact of primary resection on the outcome of patients with perforated diverticulitis. Arch Surg 139:1221–1224

    Article  PubMed  Google Scholar 

  14. De Waele JJ (2010) Early source control in sepsis. Langenbecks Arch Surg 395:489–494

    Article  Google Scholar 

  15. Dünser MW, Hasibeder WR (2009) Sympathetic overstimulation during critical illness: adverse effects of adrenergic stress. J Intensive Care Med 24:293–316

    Article  PubMed  Google Scholar 

  16. Echtenacher B, Weigl K, Lehn N, Männel DN (2001) Tumor necrosis factor-dependent adhesions as a major protective mechanism early in septic peritonitis in mice. Infect Immun 69:3550–3555

    Article  PubMed  CAS  Google Scholar 

  17. Esmon CT (2004) Interactions between the innate immune and blood coagulation systems. Trends Immunol 25:536–542

    Article  PubMed  CAS  Google Scholar 

  18. Faist E, Kupper TS, Baker CC et al (1986) Depression of cellular immunity after major injury. Its association with posttraumatic complications and its reversal with immunomodulation. Arch Surg 121:1000–1005

    PubMed  CAS  Google Scholar 

  19. Flierl MA, Schreiber H, Huber-Lang MS (2006) The role of complement, C5a and its receptors in sepsis and multiorgan dysfunction syndrome. J Invest Surg 19:255–265

    Article  PubMed  Google Scholar 

  20. Haasper C, Kalmbach M, Dikos GD et al (2010) Prognostic value of procalcitonin (PCT) and/or interleukin-6 (IL-6) plasma levels after multiple trauma for the development of multi organ dysfunction syndrome (MODS) or sepsis. Technol Health Care 18:89–100

    PubMed  CAS  Google Scholar 

  21. Hack CE, Nuijens JH, Felt-Bersma RJ et al (1989) Elevated plasma levels of the anaphylatoxins C3a and C4a are associated with a fatal outcome in sepsis. Am J Med 86:20–26

    Article  PubMed  CAS  Google Scholar 

  22. Harrington LE, Hatton RD, Mangan PR et al (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123–1132

    Article  PubMed  CAS  Google Scholar 

  23. Hauber HP, Zabel P (2009) Pathophysiology and pathogens of sepsis. Internist 50:779–787

    Article  PubMed  CAS  Google Scholar 

  24. Hawlisch H, Belkaid Y, Baelder R et al (2005) C5a negatively regulates toll-like receptor 4-induced immune responses. Immunity 22:415–426

    Article  PubMed  CAS  Google Scholar 

  25. Henckaerts L, Nielsen KR, Steffensen R et al (2009) Polymorphisms in innate immunity genes predispose to bacteremia and death in the medical intensive care unit. Crit Care Med 37:192–201

    Article  PubMed  CAS  Google Scholar 

  26. Hensler T, Hecker H, Heeg K et al (1997) Distinct mechanisms of immunosuppression as a consequence of major surgery. Infect Immun 65:2283–2291

    PubMed  CAS  Google Scholar 

  27. Hensler T, Heidecke CD, Hecker H et al (1998) Increased susceptibility to postoperative sepsis in patients with impaired monocyte IL-12 production. J Immunol 161:2655–2659

    PubMed  CAS  Google Scholar 

  28. Hoesel LM, Niederbichler AD, Ward PA (2007) Complement-related molecular events in sepsis leading to heart failure. Mol Immunol 44:95–102

    Article  PubMed  CAS  Google Scholar 

  29. Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138–150

    Article  PubMed  CAS  Google Scholar 

  30. Hotchkiss RS, Nicholson DW (2006) Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol 6:813–822

    Article  PubMed  CAS  Google Scholar 

  31. Hotchkiss RS, Opal S (2010) Immunotherapy for sepsis – a new approach against an ancient foe. N Engl J Med 363:87–89

    Article  PubMed  CAS  Google Scholar 

  32. Hotchkiss RS, Tinsley KW, Swanson PE et al (2002) Depletion of dendritic cells, but not macrophages, in patients with sepsis. J Immunol 168:2493–2500

    PubMed  CAS  Google Scholar 

  33. Huang W, Tang Y, Li L (2010) HMGB1, a potent proinflammatory cytokine in sepsis. Cytokine 51:119–126

    Article  PubMed  CAS  Google Scholar 

  34. Huang X, Venet F, Wang YL et al (2009) PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci U S A 106:6303–6308

    Article  PubMed  CAS  Google Scholar 

  35. Huber-Lang M, Sarma VJ, Lu KT et al (2001) Role of C5a in multiorgan failure during sepsis. J Immunol 166:1193–1199

    PubMed  CAS  Google Scholar 

  36. Huber-Lang MS, Younkin EM, Sarma JV et al (2002) Complement-induced impairment of innate immunity during sepsis. J Immunol 169:3223–3231

    PubMed  CAS  Google Scholar 

  37. Huston JM, Ochani M, Rosas-Ballina M et al (2006) Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med 203:1623–1628

    Article  PubMed  CAS  Google Scholar 

  38. Koerner P, Westerholt A, Kessler W et al (2008) Surgical trauma and postoperative immunosuppression. Chirurg 79:290–294

    Article  PubMed  CAS  Google Scholar 

  39. Kumar V, Sharma A (2010) Is neuroimmunomodulation a future therapeutic approach for sepsis? Int Immunopharmacol 10:9–17

    Article  PubMed  CAS  Google Scholar 

  40. Levi M, ten Cate H, Poll T van der, Deventer SJ van (1993) Pathogenesis of disseminated intravascular coagulation in sepsis. JAMA 270:975–979

    Article  PubMed  CAS  Google Scholar 

  41. Lotze MT, Tracey KJ (2005) High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 5:331–342

    Article  PubMed  CAS  Google Scholar 

  42. Maier S, Traeger T, Westerholt A, Heidecke CD (2005) Special aspects of abdominal sepsis. Chirurg 76:829–836

    Article  PubMed  CAS  Google Scholar 

  43. Marshall JC, Malam Z, Jia S (2007) Modulating neutrophil apoptosis. Novartis Found Symp 280:53–66

    Article  PubMed  CAS  Google Scholar 

  44. Meisel C, Höflich C, Volk HD (2008) Immune monitoring in SIRS and sepsis based on the PIRO model. Dtsch Med Wochenschr 133:2332–2336

    Article  PubMed  CAS  Google Scholar 

  45. Nakae H, Endo S, Inada K et al (1994) Serum complement levels and severity of sepsis. Res Commun Chem Pathol Pharmacol 84:189–195

    PubMed  CAS  Google Scholar 

  46. Niederbichler AD, Hoesel LM, Westfall MV et al (2006) An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction. J Exp Med 203:53–61

    Article  PubMed  CAS  Google Scholar 

  47. Pålsson-McDermott EM, O’Neill LA (2004) Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology 113:153–162

    Article  PubMed  Google Scholar 

  48. Park JS, Svetkauskaite D, He Q et al (2004) Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 279:7370–7377

    Article  PubMed  CAS  Google Scholar 

  49. Schuetz P, Christ-Crain M, Müller B (2007) Biomarkers to improve diagnostic and prognostic accuracy in systemic infections. Curr Opin Crit Care 13:578–585

    Article  PubMed  Google Scholar 

  50. Suárez-Santamaría M, Santolaria F, Pérez-Ramírez A et al (2010) Prognostic value of inflammatory markers (notably cytokines and procalcitonin), nutritional assessment, and organ function in patients with sepsis. Eur Cytokine Netw 21:19–26

    PubMed  Google Scholar 

  51. Thomas L (1972) Germs. N Engl J Med 287:553–555

    Article  PubMed  CAS  Google Scholar 

  52. Tracey KJ (2002) The inflammatory reflex. Nature 420:853–859

    Article  PubMed  CAS  Google Scholar 

  53. Tracey KJ (2009) Reflex control of immunity. Nat Rev Immunol 9:418–428

    Article  PubMed  CAS  Google Scholar 

  54. Trappe U, Riess H (2005) Basics in the pathophysiology of sepsis. Hamostaseologie 25:175–182

    PubMed  CAS  Google Scholar 

  55. Venet F, Chung CS, Monneret G et al (2008) Regulatory T cell populations in sepsis and trauma. J Leukoc Biol 83:523–535

    Article  PubMed  CAS  Google Scholar 

  56. Wang H, Yang H, Tracey KJ (2004) Extracellular role of HMGB1 in inflammation and sepsis. J Intern Med 255:320–331

    Article  PubMed  CAS  Google Scholar 

  57. Wang H, Yu M, Ochani M et al (2003) Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421:384–388

    Article  PubMed  CAS  Google Scholar 

  58. Ward PA (2008) Sepsis, apoptosis and complement. Biochem Pharmacol 76:1383–1388

    Article  PubMed  CAS  Google Scholar 

  59. Ward PA, Gao H (2009) Sepsis, complement and the dysregulated inflammatory response. J Cell Mol Med 13:4154–4160

    Article  PubMed  CAS  Google Scholar 

  60. Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol 25:821–852

    Article  PubMed  CAS  Google Scholar 

  61. Weighardt H, Holzmann B (2007) Role of Toll-like receptor responses for sepsis pathogenesis. Immunobiology 212:715–722

    Article  PubMed  CAS  Google Scholar 

  62. Wesche DE, Lomas-Neira JL, Perl M et al (2005) Leukocyte apoptosis and its significance in sepsis and shock. J Leukoc Biol 78:325–337

    Article  PubMed  CAS  Google Scholar 

  63. Westerholt A, Maier S, Heidecke CD (2007) Peritonitis, Sepsis, septischer Schock. Allg Viszeralchir up2date 4:237–252

    Article  Google Scholar 

  64. Winning J, Claus RA, Huse K, Bauer M (2006) Molecular biology on the ICU. From understanding to treating sepsis. Minerva Anestesiol 72:255–267

    PubMed  CAS  Google Scholar 

  65. Woiciechowsky C, Asadullah K, Nestler D et al (1998) Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat Med 4:808–813

    Article  PubMed  CAS  Google Scholar 

  66. Wood JJ, Rodrick ML, O’Mahony JB et al (1984) Inadequate interleukin 2 production. A fundamental immunological deficiency in patients with major burns. Ann Surg 200:311–320

    Article  PubMed  CAS  Google Scholar 

  67. Zantl N, Uebe A, Neumann B et al (1998) Essential role of gamma interferon in survival of colon ascendens stent peritonitis, a novel murine model of abdominal sepsis. Infect Immun 66:2300–2309

    PubMed  CAS  Google Scholar 

  68. Zhang Q, Raoof M, Chen Y et al (2010) Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464:104–107

    Article  PubMed  CAS  Google Scholar 

  69. http://www.deutsche-antisepsis-stiftung.de/modules/spaw2/up-loads/files/2008_Forschungsbericht.pdf

Download references

Danksagung

Die Autorin dankt Frau Anja Gellert für die Unterstützung bei der Erstellung der Abbildungen und Herrn Dr. rer. nat. Christian Eipel für die kritische Durchsicht des Manuskriptes.

Interessenkonflikt

Die korrespondierende Autorin gibt an, dass kein Interessenkonflikt besteht.

Author information

Authors and Affiliations

  1. Institut für Experimentelle Chirurgie, Medizinische Fakultät, Universität Rostock, Schillingallee 69a, 18055, Rostock, Deutschland

    B. Vollmar

Authors
  1. B. Vollmar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. Vollmar.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vollmar, B. Pathophysiologische Grundlagen der chirurgisch-bedingten Sepsis. Chirurg 82, 199–207 (2011). https://doi.org/10.1007/s00104-010-2010-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00104-010-2010-7

Schlüsselwörter

Keywords

Search

Navigation