Showing papers by "Jie Fan published in 2007"

Hemorrhagic Shock Induces NAD(P)H Oxidase Activation in Neutrophils: Role of HMGB1-TLR4 Signaling

Abstract: Hemorrhagic shock/resuscitation (HS/R)-induced generation of reactive oxygen species (ROS) plays an important role in posthemorrhage inflammation and tissue injury We have recently reported that HS/R-activated neutrophils (PMN), through release of ROS, serve an important signaling function in mediating alveolar macrophage priming and lung inflammation PMN NAD(P)H oxidase has been thought to be an important source of ROS following HS/R TLR4 sits at the interface of microbial and sterile inflammation by mediating responses to both bacterial endotoxin and multiple endogenous ligands, including high-mobility group box 1 (HMGB1) Recent studies have implicated HMGB1 as an early mediator of inflammation after HS/R and organ ischemia/reperfusion In the present study, we tested the hypothesis that HS/R activates NAD(P)H oxidase in PMN through HMGB1/TLR4 signaling We demonstrated that HS/R induced PMN NAD(P)H oxidase activation, in the form of phosphorylation of p47phox subunit of NAD(P)H oxidase, in wild-type mice; this induction was significantly diminished in TLR4-mutant C3H/HeJ mice HMGB1 levels in lungs, liver, and serum were increased as early as 2 h after HS/R Neutralizing Ab to HMGB1 prevented HS/R-induced phosphorylation of p47phox in PMN In addition, in vitro stimulation of PMN with recombinant HMGB1 caused TLR4-dependent activation of NAD(P)H oxidase as well as increased ROS production through both MyD88-IRAK4-p38 MAPK and MyD88-IRAK4-Akt signaling pathways Thus, PMN NAD(P)H oxidase activation, induced by HS/R and as mediated by HMGB1/TLR4 signaling, is an important mechanism responsible for PMN-mediated inflammation and organ injury after hemorrhage

Neutrophil NAD(P)H oxidase is required for hemorrhagic shock-enhanced TLR2 up-regulation in alveolar macrophages in response to LPS.

Abstract: Alveolar macrophages (AMs) play an important role in the development of posttrauma lung inflammation through initiating polymorphonuclear neutrophil (PMN) migration by direct interactions with PMN, which is in turn mediated by the expression of chemokines and cytokines. We have recently reported that hemorrhagic shock-activated PMN sensitize AM to bacteria LPS for the up-regulation of Toll-like receptor (TLR)2; in turn, this TLR2 up-regulation results in the amplification of expression of cytokines and chemokines in the AM in response to the bacterial products LPS and peptidoglycan, associated with enhanced PMN sequestration in the lung. We sought to address the mechanism underlying the augmentation of TLR2 in AM by shock-activated PMN. We found that hemorrhagic shock/resuscitation (shock) followed by a low dose of i.t. LPS markedly increased TLR2 mRNA expression in AM in wild-type (WT) mice. In contrast, in mice lacking the gp91 subunit of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase (gp91) or in neutropenic WT mice, the increase in TLR2 mRNA was attenuated. Coculture of AM with PMN derived from WT-shocked mice caused a significantly higher level of TLR2 expression in the AM in response to LPS. However, this increase in TLR2 expression was less evident when the AMs were cocultured with PMN derived from gp91 mice subjected to shock. The antioxidant polyethylene glycol catalase markedly decreased MyD88-dependent activation of IL-1 receptor associated kinase 4 and TLR2 expression in the AM in response to LPS. Thus, PMN nicotinamide adenine dinucleotide phosphate (reduced form) oxidase sensitizes hemorrhagic shock-primed AM to LPS, at least in part via enhancing IL-1 receptor associated kinase 4 activity.