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Pathogenesis of Sepsis

Pathogenesis of Sepsis. Arzu TOPELI-ISKIT, MD Hacettepe University Faculty of Medicine Department of Internal Medicine Medical Intensive Care Unit Ankara 21 April 2006.

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Pathogenesis of Sepsis

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  1. Pathogenesis of Sepsis Arzu TOPELI-ISKIT, MD Hacettepe University Faculty of Medicine Department of Internal Medicine Medical Intensive Care Unit Ankara 21 April 2006

  2. ‘’the microorganisms ... turn out ... to be rather more like bystanders ... It is our response to their presence that makes the disease’’ Lewis Thomas, NEJM 1972

  3. Sepsis • Gk: DECAY, PUTREFACTION • Hyperreactive immune system: • Innate • Adaptive (acquired)

  4. Innate Immunity • Antigen-nonspecific defense mechanisms that a host uses immediately or within several hours after exposure to almost any antigen • Recognizes few structures on many different microorganisms: Pathogen-associated molecular patterns (PAMP) • LPS (gram-negative cell wall) • Peptidoglycan • Lipotechoic acid (gram-positive cell wall) • Mannan (yeast cell wall) • ... • Pattern-recognition receptors for PAMP are present on the cells • PAMP can also be recognized by a series of soluble pattern-recognition receptors in the blood the complement pathway

  5. Innate Immunity • Phagocytic cells (neutrophils, monocytes, and macrophages) • Cells that release inflammatory mediators (basophils, mast cells, and eosinophils) • Natural killer cells (NK cells) • Molecules such as complement proteins, acute phase proteins, and cytokines

  6. Adaptive (Acquired) Immunity • Antigen-specific defense mechanisms that take several days to become protective and are designed to react with and remove a specific antigen • This is the immunity one develops throughout life. 1. Humoral immunity:Production of antibody molecules in response to an antigen and is mediated by B-lymphocytes. 2. Cell-mediated immunity:Production of cytotoxic T-lymphocytes, activated macrophages, activated NK cells, and cytokines in response to an antigen and is mediated by T-lymphocytes.

  7. Pathogenesis • Pathogens (microbial-associated molecular patterns)  sequential intracellular events in immune cells, epithelium, endothelium, and neuroendocrine system • Proinflammatory mediators to eradicate the invading microorganism (damage the host) • Antiinflammatory mediators for control (changes the immune status)

  8. Proinflammation Antiinflammation Annane. Lancet 2005;365:63

  9. Infections leading to Sepsis • Infections of chest, abdomen, genitourinary system and primary bloodstream >80% • Gram positive bacteria: 30-50% • Gram negative bacteria: 25-30% • Polymicrobial: %25 • Multidrug resistant bacteria and fungi: 25% • Viruses and parasites: 2-4% • 30% culture negative (community-acquired) Annane. Lancet 2005;365:63

  10. Signals‘Pathogen-associated molecular patterns’ (PAMP) • Endotoxin (lipopolysaccharide) • Lipoproteins • Outer membrane proteins • Flagellin • Fimbriae • Peptidoglycan • Lipoteichoic acid • Heat shock proteins • DNA fragments

  11. Pathogenesis • Initiation • Early events of sepsis – amplification • Later events of sepsis – modulation/complications • Host factors - susceptibility

  12. Initiation of Inflammation:Toll-like Receptors(TLR;recognition receptors) monocytes, macrophages, dendritic cells, neutrophils, endothelial cells Leucine rich repeat domain (LRR) Toll-IL 1 R domain (TIR) 1 2 3 4 5 6 7 8 9 10 LPS, LP, PG, CpG DNA, ds RNA, flagellin Akira. Semin Immunol 2004;16:1 Annane. Lancet 2005;365:63

  13. TLR Signaling LPS CD14 Takeda. SeminImmunol 2004;16:3 Annane. Lancet 2005;365:63 IL 8, IL 10, IL 1, TNF, IL 1Ra

  14. Cytokine Release (Amplification of Inflammation) • TNF  • IL 1 • IL 6 Pro-inflammatory mediators Other Proinflammatory Cytokines • Triggering receptor expressed on myeloid cells (TREM) 1 • High mobility group box (HMGB) 1

  15. TNF • From mononuclear cells • Macrophages • Classical mediator of septic shock • Induces itself, IL 1, IL 6 • Induces apoptosis

  16. IL 1 • Many cell types • Monocytes/macrophages • Endothelium • Epithelium • Classical mediator of fever • Endogenous pyrogen

  17. IL 6 • Many cell types • Monocytes/macrophages • Fibroblasts • Endothelial cells • Produced in response to TNF and IL 1 • Induces acute phase reactants (CRP, fibrinogen), coagulation and C5a receptor

  18. HMGB1 s • Nuclear and cytosolic protein • Cytokine mediator leading to fatal systemic inflammation • Secreted by activated macrophages • Increased serum levels in endotoxemia and sepsis • Delayed kinetics compared to TNF, IL 1 Wang. J Intern Med 2004;255:320

  19. Early Events in Sepsis CARS SIRS Proinflammatory cytokines Coagulation ...

  20. Annane. Lancet 2005;365:63

  21. Endocrin Disorders in Septic Shock Annane. Lancet 2005;365:63

  22. Other Early Events in Sepsis • Complement activation • Coagulation cascade • Kinin activation

  23. Complement Activation ‘In vivo neutralization by specific antiserum is protective in animal sepsis’ Gerard. NEJM 2003;348:167

  24. Coagulation Cascade

  25. Coagulation • Thrombin activation is the common pathway • Cleaves fibrinogen to form fibrin clot • Proinflammatory • Induces TNF and IL 6 secretion from mononuclear and endothelial cells • Regulation by • Antithrombin III • Activated protein C Fibrinolysis Coagulation

  26. Bradykinin C5 C5a Nzeako. Arch Intern Med 2001;161:2417

  27. Nitric Oxide and Sepsis • Produced in the endotheium by constitutive NOS • Blood pressure regulation and blood flow distribution • Production by inducible NOS • Hypotension, cardiodepression and vascular hyporeactivity • LPS, TNF, IL 1, INF  induce iNOS Kirkeboen. Acta Anaesthesiol Scand 1999;43:275

  28. Later Events in Sepsis • Altered cytokine patterns • Antiinflammatory cytokines: IL-10, IL-4 ... Cobb. Lancet 2004;363:2076

  29. Later Events in Sepsis • High mobility group box 1 (HMGB 1): proinflammatory Wang. J Intern Med 2004;255:320

  30. Later Events in Sepsis SIRS CARS Antiinflammatory cytokines Apoptosis Anergy Immunosuppression Secondary infections Hibernating organs ...

  31. Compensatory Events Cobb. Lancet 2004;363:2076

  32. Genetic Factors • TLR mutations • TLR4: Increased susceptibility to septic shock • TLR4 Asp299Gly polymorphism: 6-11% in Caucasions Wiersinga. Yearbook of Intensive Care and Emergency Medicine 2006;3.

  33. Summary • Innate immune response gone awry • Pro- and antiinflammatory components • 4 key early systems: • Cytokines, complement, coagulation, kinins • Later complications of immunosupression and organ dysfunction

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