Abstract
The lethal toxin (LeTx) of Bacillus anthracis plays a central role in the pathogenesis of anthrax-associated shock. Platelet-activating factor (PAF) is a potent lipid mediator that has been implicated in endotoxin-associated shock. In this study, we examined the contribution of PAF to the manifestations of lethal toxin challenge in WT mice. LeTx challenge resulted in transient increase in serum PAF levels and a concurrent decrease in PAF acetylhydrolase activity. Inhibition of PAF activity using PAF antagonists or toxin challenge of PAF receptor negative mice reversed or ameliorated many of the pathologic features of LeTx-induced damage, including changes in vascular permeability, hepatic necrosis, and cellular apoptosis. In contrast, PAF inhibition had minimal effects on cytokine levels. Findings from these studies support the continued study of PAF antagonists as potential adjunctive agents in the treatment of anthrax-associated shock.
Highlights
Plateletactivating factor (PAF) has been implicated as a potent lipid mediator of endotoxin-induced sepsis, but its role in anthraxassociated shock is unknown
Serum PAF levels at 2 and 16 h were not significantly different between mice treated with lethal toxin (LeTx) and controls
Serum PAF acetylhydrolase (PAF-AH) activity was significantly lower in LeTx-treated mice (129 Ϯ 24 mol/min/ml) compared with PBS-treated (155 Ϯ 22 mol/min/ml) and untreated mice (178 Ϯ 18 mol/min/ml) (p Ͻ 0.05) (Fig. 1C)
Summary
PAF has been implicated as a potent lipid mediator of endotoxin-induced sepsis, but its role in anthraxassociated shock is unknown. LeTx challenge resulted in transient increase in serum PAF levels and a concurrent decrease in PAF acetylhydrolase activity. Inhibition of PAF activity using PAF antagonists or toxin challenge of PAF receptor negative mice reversed or ameliorated many of the pathologic features of LeTx-induced damage, including changes in vascular permeability, hepatic necrosis, and cellular apoptosis. PAF inhibition had minimal effects on cytokine levels Findings from these studies support the continued study of PAF antagonists as potential adjunctive agents in the treatment of anthrax-associated shock. PAF is produced in response to stimuli by a variety of cell types, including monocytes/macrophages, polymorphonuclear leukocytes, eosinophils, basophils, platelets, mast cells, vascular endothelial cells, and lymphocytes This lipid mediator exerts diverse biologic effects and has been implicated in several pathologic conditions including systemic inflammatory response and shock. Given the overlap in the clinical syndromes induced by LeTx and PAF, we sought to determine whether PAF contributes to the pathologic disturbances induced by LeTx
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