Abstract
Lipopolysaccharide (LPS) signaling through Toll-like receptor-4 (TLR-4) has been implicated in the pathogenesis of many infectious diseases. Some believe that TLR-mediated pathogenicity is due, in part, to the lipid pro-inflammatory mediator platelet-activating factor (PAF), but this has been questioned. To test the direct contribution of PAF in endotoxemia in murine models, we injected PAF intraperitoneally into Swiss albino mice in the presence and absence of LPS. PAF alone (5 μg/mouse) caused death within 15–20 min, but this could be prevented by pretreating mice with PAF-receptor (PAF-R) antagonists or PAF-acetylhydrolase (PAF-AH). A low dose of LPS (5 mg/kg body wt) did not impair PAF-induced death, whereas higher doses (10 or 20 mg/kg body wt) delayed death, probably via LPS cross-tolerance. Cross-tolerance occurred only when PAF was injected simultaneously with LPS or within 30 min of LPS injection. Tolerance does not appear to be due to an abundant soluble mediator. Histologic examination of lungs and liver and measurement of circulating TNF-α and IL-10 levels suggested that the inflammatory response is not diminished during cross-tolerance. Interestingly, aspirin, a non-specific cyclooxygenase (COX) inhibitor, partially blocked PAF-induced sudden death, whereas NS-398, a specific COX-2 inhibitor, completely protected mice from the lethal effects of PAF. Both COX inhibitors (at 20 mg/kg body wt) independently amplified the cross-tolerance exerted by higher dose of LPS, suggesting that COX-derived eicosanoids may be involved in these events. Thus, PAF does not seem to have a protective role in endotoxemia, but its effects are delayed by LPS in a COX-sensitive way. These findings are likely to shed light on basic aspects of the endotoxin cross-tolerance occurring in many disease conditions and may offer new opportunities for clinical intervention.
Highlights
Microbial products induce a shift in the innate immune system towards a pro-inflammatory phenotype by activating a family of pattern-recognizing receptors popularly known as Toll-like receptors [1].The downstream signaling events of these receptors are critical in the pathogenesis of many infectious disease complications, such as endotoxemia/sepsis [2]
A few reports have claimed that platelet-activating factor (PAF) and PAF-like lipids play a protective role in LPS-mediated endotoxemia [50,51,52,53]
Have shown that endotoxins are good inducers of PAF biosynthesis in human neutrophils [9, 91], and results from overexpressing or deleting PAF-R in animal models suggest that PAF plays a role in endotoxemia [38,40]
Summary
Microbial products induce a shift in the innate immune system towards a pro-inflammatory phenotype by activating a family of pattern-recognizing receptors popularly known as Toll-like receptors [1].The downstream signaling events of these receptors are critical in the pathogenesis of many infectious disease complications, such as endotoxemia/sepsis [2]. A pleiotropic mediator often implicated in sepsis is the bacterial endotoxin lipopolysaccharide (LPS) [4,5]. LPS interacts with the Toll-like receptor-4 (TLR-4), along with other accessory components, to generate a battery of pro-inflammatory cytokines and lipid mediators that promote a systemic inflammatory response–the hallmark of sepsis [6]. A better understanding is needed of sepsis in general and the role of TLR-4 agonists in this process before new therapeutics against sepsis is developed
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