title: Cutting edge: TLR4 deficiency confers susceptibility to lethal oxidant lung injury.
abstract: TLRs have been studied extensively in pathogen-mediated host responses. We use a murine model of lethal oxidant-mediated injury to demonstrate for the first time that mammalian TLR4 is required for survival and lung integrity. Administering high levels of inspired oxygen, or hyperoxia, is commonly used as a life-sustaining measure in critically ill patients. However, prolonged exposures can lead to respiratory failure and death. TLR4-deficient mice exhibited increased mortality and lung injury during hyperoxia. The enhanced susceptibility of TLR4-deficient mice to hyperoxia was associated with an inability to up-regulate Bcl-2 and phospho-Akt. Restoration of Bcl-2 and phospho-Akt levels by the exogenous transfer of the antioxidant gene heme oxygenase-1 markedly attenuated hyperoxia-induced injury, apoptosis, and mortality in TLR4-deficient mice. Taken together, our results suggest a protective role of TLR4 in oxidant-mediated injury, providing novel mechanistic links among innate immunity, oxidant stress, and apoptosis.
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Xuchen
authors.initials: X
authors.lastname: Zhang
authors.forename: Peiying
authors.initials: P
authors.lastname: Shan
authors.forename: Salman
authors.initials: S
authors.lastname: Qureshi
authors.forename: Robert
authors.initials: R
authors.lastname: Homer
authors.forename: Ruslan
authors.initials: R
authors.lastname: Medzhitov
authors.forename: Paul W
authors.initials: PW
authors.lastname: Noble
authors.forename: Patty J
authors.initials: PJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D018014:Gene Transfer Techniques; D020022:Genetic Predisposition to Disease; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D018496:Hyperoxia / Q000378:metabolism / Q000401:mortality; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D016877:Oxidants / Q000633:toxicity*; D051197:Toll-Like Receptor 4 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
chemical_list: D016877:Oxidants; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051547:Heme Oxygenase-1