Mechanisms for chlorinated lipids in sepsis

Abstract

Sepsis induces the formation of proinflammatory chlorinated lipids, stimulates adhesive interactions between the endothelium and leukocytes/platelets, causes mast cell activation, disrupts the microvascular barrier and causes acute lung injury. Using a cecal ligation and puncture (CLP) model of polymicrobial sepsis, the aims of this study were to determine whether: 1) the proinflammatory responses to sepsis are instigated by myeloperoxidase (MPO), an enzyme that produces hypochlorous acid, which can attack membrane plasmalogens to produce chlorinated lipids, 2) MPO plays an important role in the generation of cytokines and chemokines that have been proposed as mediators of the inflammatory responses to sepsis, and 3) plasminogen-activator inhibitor-1 (PAI-1) and mast cells contribute to CLP-induced adhesive interactions between leukocytes/platelets and the endothelium. A subproject to Aim 3 sought to identify the contribution of PAI-1 and mast cells to adhesive interactions induced by chlorinated lipids in lieu of CLP, as an approach to support the concept that MPO-derived chlorinated lipids may serve as an important mediator of sepsis-induced inflammatory responses. Our results are consistent with the concept the CLP promotes MPO-dependent release of proinflammatory PAI-1, cytokines, and chemokines, which in turn activate mast cells to elicit leukocyte/platelet adhesive interactions with the endothelium, neutrophil migration into the tissues and disruption of microvascular barrier function.