29 Pathogenesis of sepsis Impaired vascular barrier function is a key pathogenic mechanism in sepsis, associated with protein leakage into the extravascular space, tissue edema and diminished microvascular perfusion [25]. Important regulators of vascular barrier function are sphingosine-1-phosphate (S1P) and angiopoietin-1 [25, 33]. SP1 activates the endothelial S1P receptor 1, thereby preserving vascular integrity [33]. Angiopoietin-1 activates TIE2, supporting barrier function. Angiopoietin-2 antagonizes angiopoietin-1 and a high angiopoietin-2/angiopoietin-1 ratio has been used as a marker for vascular barrier dysfunction in patients with sepsis [34]. Neutrophil extracellular traps Activation of the coagulation system and vascular injury are amplified by the release of neutrophil extracellular traps (NETs) by neutrophils [35]. NETs are composed of DNA, histones and neutrophil-derived proteinases and can protect the host by eliminating pathogens. However, NETs may also contribute to collateral damage and thrombosis in the dysregulated immune response in sepsis [35]. Immune suppression Much attention has been drawn to immune suppression in patients which sepsis, which in many patients can already be detected on admission to the ICU and is a prominent feature in those patients that remain in the ICU for extended periods of time [2, 36]. Targeted immune-enhancing therapy may be beneficial for selected patients with immune suppression [2, 36]. Transcriptomic analysis of peripheral blood leucocytes of septic patients recently resulted in the classifications of distinct sepsis endotypes with implications for main pathophysiological mechanisms and prognosis [37, 38]. These studies further confirmed the existence of subgroups of sepsis patients with a predominant immune suppressive phenotype [37, 38]. Apoptosis of immune cells Sepsis associated immune suppression involves several cell types. During sepsis massive apoptosis leads to depletion of immune cells, especially CD4+ and CD8+ T cells and B cells. This depletion is seen in lymphoid organs and body sites, such as spleen, thymus, lymph nodes and gut-associated lymphoid tissue [36, 39]. T regulatory (Treg) cells are more resistant to sepsis-induced apoptosis which, combined with the substantial apoptosis of CD4+ and CD8+ T cells and B cells, lead to a more immunosuppressive phenotype. Furthermore, surviving CD4+ and CD8+ T cells shift from a Th1 proinflammatory phenotype to the more immunosuppressive Th2 phenotype. Inhibition of lymphocyte apoptosis was associated with better outcomes in various experimental sepsis models, suggesting a causal relationship between lymphocyte apoptosis and sepsis mortality [2, 36]. A recently identified potential therapeutic target in sepsis is the programmed cell death 1 (PD1) – PD1 ligand (PDL1) pathway. Patients with sepsis showed enhanced expression of PD1 on CD4+ T cells together with increased expression of PDL1 on macrophages and endothelial cells [39]. Enhanced PD1 – PDL1 interaction 2
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