title: Hemorrhagic shock activation of NLRP3 inflammasome in lung endothelial cells.
abstract: Hemorrhagic shock (HS) due to major trauma and surgery predisposes the host to the development of systemic inflammatory response syndrome (SIRS), including acute lung injury (ALI), through activating and exaggerating the innate immune response. IL-1β is a crucial proinflammatory cytokine that contributes to the development of SIRS and ALI. Lung endothelial cells (EC) are one important source of IL-1β, and the production of active IL-1β is controlled by the inflammasome. In this study, we addressed the mechanism underlying HS activation of the inflammasome in lung EC. We show that high mobility group box 1 acting through TLR4, and a synergistic collaboration with TLR2 and receptor for advanced glycation end products signaling, mediates HS-induced activation of EC NAD(P)H oxidase. In turn, reactive oxygen species derived from NAD(P)H oxidase promote the association of thioredoxin-interacting protein with the nucleotide-binding oligomerization domain-like receptor protein NLRP3 and subsequently induce inflammasome activation and IL-1β secretion from the EC. We also show that neutrophil-derived reactive oxygen species play a role in enhancing EC NAD(P)H oxidase activation and therefore an amplified inflammasome activation in response to HS. The present study explores a novel mechanism underlying HS activation of EC inflammasome and thus presents a potential therapeutic target for SIRS and ALI induced after HS.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Xiang
authors.forename: Xiaolian
authors.initials: X
authors.lastname: Shi
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Li
authors.forename: Jia
authors.initials: J
authors.lastname: Xu
authors.forename: Lianhua
authors.initials: L
authors.lastname: Yin
authors.forename: Guozhi
authors.initials: G
authors.lastname: Xiao
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Scott
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wilson
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D024243:HMGB1 Protein / Q000502:physiology; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D012771:Shock, Hemorrhagic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D024243:HMGB1 Protein; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human