Fig. 2

Vascular endothelial dysfunction in the pathogenesis of septic organ injury. The vascular endothelium plays a crucial role in inflammation, immunothrombosis, and vascular barrier integrity. During sepsis, the activation of a highly complex inflammatory cascade by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) triggers the production of pro-inflammatory, proapoptotic, and procoagulant mediators by both immune cells and vascular endothelial cells (ECs). Toll-like receptor (TLR) signaling causes nuclear translocation of transcription factor NF-kb, leading to a deleterious cytokine release syndrome. The luminal surface of the vascular endothelium is lined by the endothelial glycocalyx (eGC), a gel-like carbohydrate-rich structure. In sepsis, heparanase-1 (HPA-1) activity is upregulated inducing degradation of the eGC. Glycocalyx shedding exposes embedded adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) which both enable leukocyte rolling, adhesion, and transmigration. Loss of the eGC, junctional disassembly, and EC apoptosis result in capillary barrier dysfunction, increased permeability, and interstitial tissue edema. Besides amplifying the inflammatory host response, ECs also promote a prothrombotic state leading to microvascular clotting and frequently disseminated intravascular coagulation (DIC). A lack of cleavage of von Willebrand factor (VWF) due to reduced levels of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) contributes to the accumulation of ultra-large VWF (ULVWF) multimers facilitating platelet adhesion to injured endothelium. The upregulation of tissue factor which initiates extrinsic coagulation and plasminogen activator inhibitor 1 (PAI-1), the main inhibitor of fibrinolysis, further augments the process of sepsis-induced immunothrombosis