title: Rtp801 suppression of epithelial mTORC1 augments endotoxin-induced lung inflammation.
abstract: The mechanistic target of rapamycin (mTOR) is a central regulator of cellular responses to environmental stress. mTOR (and its primary complex mTORC1) is, therefore, ideally positioned to regulate lung inflammatory responses to an environmental insult, a function directly relevant to disease states such as the acute respiratory distress syndrome. Our previous work in cigarette smoke-induced emphysema identified a novel protective role of pulmonary mTORC1 signaling. However, studies of the impact of mTORC1 on the development of acute lung injury are conflicting. We hypothesized that Rtp801, an endogenous inhibitor of mTORC1, which is predominantly expressed in alveolar type II epithelial cells, is activated during endotoxin-induced lung injury and functions to suppress anti-inflammatory epithelial mTORC1 responses. We administered intratracheal lipopolysaccharide to wild-type mice and observed a significant increase in lung Rtp801 mRNA. In lipopolysaccharide-treated Rtp801(-/-) mice, epithelial mTORC1 activation significantly increased and was associated with an attenuation of lung inflammation. We reversed the anti-inflammatory phenotype of Rtp801(-/-) mice with the mTORC1 inhibitor, rapamycin, reassuring against mTORC1-independent effects of Rtp801. We confirmed the proinflammatory effects of Rtp801 by generating a transgenic Rtp801 overexpressing mouse, which displayed augmented inflammatory responses to intratracheal endotoxin. These data suggest that epithelial mTORC1 activity plays a protective role against lung injury, and its inhibition by Rtp801 exacerbates alveolar injury caused by endotoxin.
authors.affiliation: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Nadon
authors.affiliation: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Mario J
authors.initials: MJ
authors.lastname: Perez
authors.affiliation: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hernandez-Saavedra
authors.affiliation: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Lynelle P
authors.initials: LP
authors.lastname: Smith
authors.affiliation: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Yimu
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Sanders
authors.affiliation: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Aneta
authors.initials: A
authors.lastname: Gandjeva
authors.affiliation: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Jacob
authors.initials: J
authors.lastname: Chabon
authors.affiliation: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Koyanagi
authors.affiliation: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Graham
authors.affiliation: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
authors.affiliation: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado. Electronic address: eric.schmidt@ucdenver.edu.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Schmidt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D004731:Endotoxins / Q000633:toxicity; D005455:Fluorescent Antibody Technique; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000276:immunology / Q000378:metabolism*; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C450979:Ddit4l protein, mouse; D004731:Endotoxins; D046912:Multiprotein Complexes; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases