The role of endotoxin in septic shock

Abstract

Septic shock can be caused by a variety of mechanisms including direct effects of bacterial toxins such as endotoxin. Annually, approximately 5-7 million patients worldwide develop sepsis with very high endotoxin activity in the blood and more than half die. The term endotoxic septic shock has been used for these patients but it is important to emphasize that endotoxin may be a factor in all forms of septic shock including non-bacterial etiologies like COVID-19 since translocation of bacterial products is a common feature of septic shock. A pattern of organ failure including hepatic dysfunction, acute kidney injury and various forms of endothelial dysfunction ranging from disseminated intravascular coagulation to thrombotic microangiopathy characterize endotoxic septic shock. However, while characteristic, the clinical phenotype is not unique to patients with high endotoxin, and the diagnosis relies on the measurement of endotoxin activity in addition to clinical assessment. Therapies for endotoxic septic shock are limited with immune modulating therapies under investigation and extracorporeal blood purification still controversial in many parts of the world.

Keywords: Endotoxic septic shock; Endotoxin; Phenotypes; Sepsis; Septic shock.

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

Fig. 2

Relationship between endotoxin load and clinical manifestations. EAA, endotoxin activity assay