Factors believed to play major roles in the pathophysiology of septic shock include the following: • Inflammatory and counterinflammatory responses. In sepsis, various microbial cell wall constituents engage receptors on cells of the innate immune system, triggering proinflammatory responses. Likely initiators of inflammation in sepsis are signaling pathways that lie downstream of Toll-like receptors (TLRs) (Chapter 5), which recognize a host of microbe-derived substances containing so-called “pathogen-associated molecular patterns” (PAMPs), as well as G-protein–coupled receptors that detect bacterial peptides, and C-type lectin receptors such as Dectins. On activation, innate immune cells produce numerous cytokines, including TNF, IL-1, IFNγ, IL-12, and IL-18, as well as other inflammatory mediators such as high-mobility group box 1 protein (HMGB1). Markers of acute inflammation such as C-reactive protein and procalcitonin are also elevated. The latter is a clinically useful indicator of septic shock. Reactive oxygen species and lipid mediators such as prostaglandins and platelet-activating factor (PAF) are also elaborated. These effector molecules induce endothelial cells (and other cell types) to upregulate adhesion molecule expression and further stimulate cytokine and chemokine production. The complement cascade is also activated by microbial components, both directly and through the proteolytic activity of plasmin (Chapter 3), resulting in the production of anaphylotoxins (C3a, C5a), chemotactic fragments (C5a), and opsonins (C3b), all of which contribute to the proinflammatory state. In addition, microbial components can activate coagulation directly through factor XII and indirectly through altered endothelial function (discussed later). The accompanying widespread activation of thrombin may further augment inflammation by triggering protease activated receptors on inflammatory cells.
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TISSUE ISCHEMIA Procoagulant Anti-fibrinolytic Adrenal insufficiency MULTIORGAN FAILURE IL-10, apoptosis, STNFR Secondary anti-inflammatory mediators IL-6, IL-8, NO, PAF, reactive oxygen species, etc. Microbial products (PAMPs) Factor XII TNF, IL-1, HMGB1 Endothelial activation Neutrophil and monocyte activation Cytokines and cytokine-like mediators Complement activation Direct and indirect MICROVASCULAR THROMBOSIS (DIC) IMMUNOSUPPRESSION VASODILATION INCREASED PERMEABILITY DECREASED PERFUSION SYSTEMIC EFFECTS Fever, diminished myocardial contractility, metabolic abnormalities TFPI, thrombomodulin, protein C TF PAI-1 C3 C3a
Fig. 4.19 Majorpathogenicpathwaysinsepticshock.Microbialproductsactivateendothelialcellsandcellularandhumoralelementsoftheinnateimmunesystem,initiatingacascadeofeventsthatleadtoend-stagemultiorganfailure.Additionaldetailsareprovidedinthetext.DIC, Disseminatedintravascularcoagulation;HMGB1, high-mobilitygroupbox1protein;NO, nitricoxide;PAF, platelet-activatingfactor;PAI-1, plasminogenactivatorinhibitor-1;PAMP, pathogen-associatedmolecularpattern;STNFR, solubletumornecrosisfactorreceptor;TF, tissuefactor;TFPI, tissuefactorpathwayinhibitor.