Abstract
Lipopolysaccharide, the main component of the outer membrane of Gram-negative bacteria is a highly potent endotoxin responsible for organ dysfunction in sepsis. It is present in the blood stream not only in Gram-negative infections, but also in Gram-positive and fungal infections, presumably due to sepsis-related disruption of the intestinal barrier. Various pathways, both extra- and intracellular, are involved in sensing endotoxin and non-canonical activation of caspase-mediated pyroptosis is considered to have a major role in sepsis pathophysiology. Endotoxin induces specific pathological alterations in several organs, which contributes to poor outcomes. The adverse consequences of endotoxin in the circulation support the use of anti-endotoxin therapies, yet more than 30 years of experience with endotoxin adsorption therapies have not provided clear evidence in favor of this treatment modality. The results of small studies support timely endotoxin removal guided by measuring the levels of endotoxin; unfortunately, this has not been proven in large, randomized studies. The presence of endotoxemia can be demonstrated in the majority of patients with COVID-19, yet only case reports and case series describing the effects of endotoxin removal in these patients have been published to date. The place of blood purification therapies in the treatment of septic shock has not yet been determined.
Highlights
Lipopolysaccharide, the main component of the outer membrane of Gram-negative bacteria is a highly potent endotoxin responsible for organ dysfunction in sepsis
The aim of this review is to summarize the current knowledge on the pathophysiology of endotoxin and the existing evidence on the efficacy of extracorporeal blood purification treatment relative to the adverse impact of endotoxin on organ function
Murine studies demonstrated that endotoxin uses both toll-like receptor 4 (TLR4) and caspase-11/gasdermin D (GsdmD) pathways to induce the release of high mobility-group-box-1 (HMGB1) from hepatocytes—the major source of circulating HMGB1 in sepsis [50]
Summary
Lipopolysaccharide is sensed via extracellular and intracellular pathways that lead to the activation of the immune response. Binding Protein (LBP), carried to form a complex with either a soluble or membrane bound cluster of differentiation-14 (CD14), and subsequently transferred to the toll-like receptor 4/myeloid differentiation-2 (MD-2) complex, which promotes the TLR4/MD-2 dimerization necessary for activating intracellular MyD88-dependent and TRIF-dependent pathways. Both pathways lead to the production and release of pro-inflammatory cytokines and type I interferones (IFNs), respectively [26,27,28]. LPS sensing by TRP channels provides an immediate response to invading pathogens, which is faster and independent of the canonical TLR4 immune pathway [31]
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