title: Hemorrhagic shock-activated neutrophils augment TLR4 signaling-induced TLR2 upregulation in alveolar macrophages: role in hemorrhage-primed lung inflammation.
abstract: Hemorrhagic shock renders patients susceptible to the development of acute lung injury in response to a second inflammatory stimulus by as yet unclear mechanisms. We investigated the role of neutrophils (PMN) in alveolar macrophage (AMphi) priming, specifically, the role in mediating Toll-like receptor (TLR)4 and TLR2 cross talk in AMphi. Using a mouse model of hemorrhagic shock followed by intratracheal administration of LPS, we explored a novel function of shock-activated PMN in the mechanism of TLR2 upregulation induced by LPS-TLR4 signaling in AMphi. We showed that antecedent hemorrhagic shock enhanced LPS-induced TLR2 upregulation in AMphi. In neutropenic mice subjected to shock, the LPS-induced TLR2 expression was significantly reduced, and the response was restored upon repletion with PMN obtained from shock-resuscitated mice but not by PMN from sham-operated mice. These findings were recapitulated in mouse AMphi cocultured with PMN. The enhanced TLR2 upregulation in AMphi augmented the expression of macrophage inflammatory protein-2, TNF-alpha, and macrophage migration inhibitory factor in the AMphi in response to sequential challenges of LPS and peptidoglycan, a prototypical TLR2 ligand, which physiologically associated with amplified AMphi-induced PMN migration into air pouch and lung alveoli. Thus TLR2 expression in AMphi, signaled by TLR4 and regulated by shock-activated PMN, is an important positive-feedback mechanism responsible for shock-primed PMN infiltration into the lung after primary PMN sequestration.
authors.affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15240, USA. jif7@pitt.edu
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Li
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wilson
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation; D020556:Neutrophil Infiltration; D011014:Pneumonia / Q000209:etiology; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000150:complications / Q000503:physiopathology*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4