27 Pathogenesis of sepsis Hyperinflammation Sepsis is associated with a strong activation of the immune system, by stimulation of PRRs by PAMPs and DAMPs, leading to the activation of target genes coding for proinflammatory cytokines such as tumor necrosis factor (TNF), IL-1β, IL-12 and IL18[2]. Cytokines are small proteins that can regulate the host response both locally and systemically, after their release from various cell types such as monocytes and neutrophils. These cells can further attribute to activation of the immune system by expression of the Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) that amplifies TLR- and NLR-mediated inflammatory response [15]. Several mechanisms regulate the activation of PRRs to avoid overstimulation, including the negative regulators MyD88 short (MyD88s), ST2, single-immunoglobulin-interleukin (IL)-1 receptor-related-molecule (SIGIRR), toll-interacting protein (TOLLIP), suppressorof-cytokine signaling (SOCS), A20 and IRAK-M [16]. If the delicate balance between activation and inhibition of the inflammatory response is disturbed, the pleiotropic hyperinflammatory response in sepsis ensues. This includes activation of the complement and coagulation systems and disturbance of vascular permeability [2], which have been considered important factors in sepsis mortality. Complement system The complement system comprises over 40 components that, when activated, work as a cascade and contribute to the innate immune surveillance system [17, 18]. A close collaboration between the complement system and other proinflammatory stimuli such as cytokines is necessary: the complement system tags dangerous cells or pathogens, and phagocytic cells can respond more properly after activation by proinflammatory mediators. This teamwork is dysregulated in sepsis resulting in inefficient use of the complement system. The complement system contributes directly to the activation of the immune system by the release of anaphylatoxins C3a and C5a. Anaphylatoxins are proinflammatory molecules that activate surrounding cells when they reach a threshold concentration, can lead to the recruitment of other immune cells (macrophages, basophils, neutrophils, eosinophils and mast cells) and can activate endothelial and epithelial cells and platelets [17, 18]. The harmful role of C5a in sepsis has been linked to neutrophil dysfunction, apoptosis of lymphoid cells, exacerbation of systemic inflammation, cardiomyopathy, disseminated intravascular coagulation (DIC) and complications associated with multiple organ failure [19]. Several experimental sepsis studies have highlighted the beneficial effect of blockage of C5a signaling on outcome [20]. As such, C5a is considered a potential therapeutic target in sepsis. Coagulation system and vascular endothelium Activation of PRRs leads to upregulation of inflammatory mediators which results in a systemic inflammatory response, including activation of the coagulation system and concurrent downregulation of anticoagulant mechanisms [21]. Coagulation abnormalities can range from mild to clinically relevant fulminant coagulopathies. DIC is the most severe manifestation of disturbed hemostasis with microvascular thrombosis and, through consumption of clotting factors and platelets, simultaneous 2
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