Fig. 1

Mechanisms of endotoxic septic shock. Dominant mechanisms of LPS-induced cell damage. Endotoxin lipopolysaccharide (LPS) is released from Gram-negative bacteria in response to proliferation but greatly increased with bacterial cell death. TLR4/MD-2 (neutrophil in the lower field) is the primary receptor for extracellular LPS which engages multiple overlapping pathways leading to expression of cytokines and other inflammatory molecules. However, cytoplasmic LPS (left) is also sensed by caspase activation and recruitment domains and caspases 4 and 5 leading to NLRP3-mediated inflammasome activation. This process may also directly result in mitochondrial dysfunction as a TNF-BAX-mediated process shown in the lower left. LPS is also a potent activator of complement and C5a can directly induce NFKB-mediated inflammation. C3a signaling also leads to histamine release from mast cells (right). Complement activation can affect coagulation in numerous ways PAI-I and TF are induced, platelets become activated, and the clotting cascade is engaged. Fibrinogen fragments can induce endothelial barrier dysfunction mediated by alpha-v and beta 3 integrins in a RhoA-dependent fashion. αvβ3, alpha-v beta 3 integrin; AP-1, Activator protein 1 transcription factor; BAX, Bcl-associated X protein; CARD, caspase activation and recruitment domain; iNOS, inducible nitric oxide synthetase; IRF3, interferon regulatory factor 3; MAC, membrane attack complex; MCP-1, monocyte chemoattractant protein 1, MyD88, myeloid differentiation primary response 88; NFKB, nuclear factor kappa B; NLRP3, NLR family pyrin domain containing 3; NO, nitric oxide; PAI-1, plasminogen activator inhibitor-1; RhoA, Ras homolog gene family, member A; TF, tissue factor; TRAM/TRAP/TRIF, TLR adaptor molecules