23 Pathogenesis of sepsis Introduction Before the turn of the century, the pathogenesis of sepsis was considered to be driven by an abundant inflammatory response following the invasion of pathogens [1]. Current consensus acknowledges the occurrence of two opposite host reactions to severe infection with proinflammatory and anti-inflammatory features [2]. In sepsis, the normally careful inflammatory balance is disturbed and hyperinflammation together with immune suppression ensue. This dysregulated immune response to infection is associated with a failure to return to homeostasis and harms the host, resulting in the life-threatening condition called sepsis [3]. While insights in the pathogenesis of sepsis have rapidly grown, this complex syndrome is not yet fully understood and our increased understanding of pathophysiological mechanisms underlying sepsis has thus far failed to improve health outcome. This chapter provides a brief overview of the pathogenesis of sepsis (Figure 1). A B CBRAIN LUNG HEART LIVER KIDNEY INTESTINE BONEMARROW delirium encephalopathy ARDS high output distributive shock coagulopathy cholestatis AKI compromised intestinal barrier suppression cytopenia PRO-INFLAMMATORY RESPONSE IMMUNE SUPPRESSION PATHOGEN load virulence PAMPs e.g. LPS, lipopeptide, peptidoglycan, LTA, flagella, DNA, RNA Leukocyte activation Complement activation Coagulation activation Necrotic cell death Reprogramming of monocytes and macrophages Apoptosis immune cells Changes in cellular metabolism DAMPs e.g. HSPs, fibrinogen, hyaluronic acid, HMGB1 PRRs Figure 1. Pathogenesis of sepsis. (A) Sepsis is defined as a dysregulated host response to infection, leading to life-threatening organ dysfunction. The normally careful inflammatory balance is disturbed and this dysregulation is associated with a failure to return to homeostasis. Hyperinflammation and immune suppression ensue, to an extent that is detrimental to the host. (B) Once a pathogen has succeeded to cross the mucosal barrier of the host, it can cause sepsis depending on its load and virulence. The host defense system can recognize molecular components of invading pathogens (PAMPs) with specialized receptors (PRRs). Stimulation of PRRs has pro-inflammatory and immune suppressive consequences. It leads to activation of target genes coding for proinflammatory cytokines (leukocyte activation), inefficient use of the complement system, activation of the coagulation system and concurrent downregulation of anticoagulant mechanisms and necrotic cell death. This starts a vicious cycle with further progression to sepsis, due to the release of endogenous molecules by injured cells (DAMPs or 2
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