Role of platelet-activating factor in protecting against lipopolysaccharide-induced endotoxic shock

Abstract

AbstractPlatelet-activating factor (PAF) has been long believed to be associated with many pathophysiological processes during septic shock. Here we present novel activities for PAF in the LPS-mediated endotoxic shock. In vivo PAF treatment immediately after LPS challenge markedly improved the survival rate against mortality from endotoxic shock. In addition, this treatment prominently attenuated LPS-induced profound hypotension, excessive polymorphonuclear neutrophil infiltration, severe multiple organ failure, and lymphocyte apoptosis. These protective effects of PAF was correlated with significantly decreases in the production of the inflammatory mediators such as TNF-α, IL-1β, IL-12, and IFN-γ, while increasing production of the anti-inflammatory cytokine IL-10 in vivo and in vitro. In response to LPS, PAF inhibits ERK1/2 and p38 MAPK activation, which is critical for proinflammatory cytokines production. Furthermore, PAF upregulates SOCS1 and SOCS3, which are essential for cross-talk inhibition in LPS-induced cytokine signaling. Taken together, these results suggest that PAF may provide protection against endotoxic shock via a complex mechanism involving modulation of inflammatory and anti-inflammatory mediators, as well as balanced regulation between activation and subsequent deactivation of the signaling pathways in response to LPS.