title: Inhibition of mammalian target of rapamycin augments lipopolysaccharide-induced lung injury and apoptosis.
abstract: Acute lung injury during bacterial infection is associated with neutrophilic inflammation, epithelial cell apoptosis, and disruption of the alveolar-capillary barrier. TLR4 is required for lung injury in animals exposed to bacterial LPS and initiates proinflammatory responses in part via the transcription factor NF-κB. Ligation of TLR4 also initiates a proapoptotic response by activating IFN-β and STAT1-dependent genes. We recently demonstrated that mammalian target of rapamycin (mTOR), a key controller of cell growth and survival, can physically interact with STAT1 and suppress the induction of STAT1-dependent apoptosis genes. We therefore hypothesized that the mTOR inhibitor rapamycin would increase LPS-induced apoptosis and lung injury in vivo. Rapamycin increased lung injury and cellular apoptosis in C57BL/6J mice exposed to intratracheal LPS for 24 h. Rapamycin also augmented STAT1 activation, and the induction of STAT1-dependent genes that mediate cellular apoptosis (i.e., Fas, caspase-3). LPS-induced lung injury was attenuated in STAT1 knockout mice. In addition, LPS and IFN-β-induced apoptosis was absent in cultured cells lacking STAT1, and, unlike in wild-type cells, a permissive effect of rapamycin was not observed. In contrast to its effect on STAT1, rapamycin inhibited NF-κB activation in vivo and reduced selected markers of inflammation (i.e., neutrophils in the bronchoalveolar lavage fluid, TNF-α). Therefore, although it inhibits NF-κB and neutrophilic inflammation, rapamycin augments LPS-induced lung injury and apoptosis in a mechanism that involves STAT1 and the induction of STAT1-dependent apoptosis genes.
authors.affiliation: Critical Care Division, Department of Medicine, McGill University Health Centre-Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Fielhaber
authors.forename: Scott F
authors.initials: SF
authors.lastname: Carroll
authors.forename: Anders B
authors.initials: AB
authors.lastname: Dydensborg
authors.forename: Mitra
authors.initials: M
authors.lastname: Shourian
authors.forename: Alexandra
authors.initials: A
authors.lastname: Triantafillopoulos
authors.forename: Sharon
authors.initials: S
authors.lastname: Harel
authors.forename: Sabah N
authors.initials: SN
authors.lastname: Hussain
authors.forename: Maxime
authors.initials: M
authors.lastname: Bouchard
authors.forename: Salman T
authors.initials: ST
authors.lastname: Qureshi
authors.forename: Arnold S
authors.initials: AS
authors.lastname: Kristof
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D018893:Bronchoalveolar Lavage; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016899:Interferon-beta; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus