Abstract
Rtp801 (also known as Redd1, and encoded by Ddit4), a stress-related protein triggered by adverse environmental conditions, inhibits mammalian target of rapamycin (mTOR) by stabilizing the TSC1-TSC2 inhibitory complex and enhances oxidative stress–dependent cell death. We postulated that Rtp801 acts as a potential amplifying switch in the development of cigarette smoke–induced lung injury, leading to emphysema. Rtp801 mRNA and protein were overexpressed in human emphysematous lungs and in lungs of mice exposed to cigarette smoke. The regulation of Rtp801 expression by cigarette smoke may rely on oxidative stress–dependent activation of the CCAAT response element in its promoter. We also found that Rtp801 was necessary and sufficient for nuclear factor-κB (NF-κB) activation in cultured cells and, when forcefully expressed in mouse lungs, it promoted NF-κB activation, alveolar inflammation, oxidative stress and apoptosis of alveolar septal cells. In contrast, Rtp801 knockout mice were markedly protected against acute cigarette smoke–induced lung injury, partly via increased mTOR signaling, and, when exposed chronically to cigarette smoke, against emphysema. Our data support the notion that Rtp801 may represent a major molecular sensor and mediator of cigarette smoke–induced lung injury.
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Acknowledgements
We thank T. Stevens (University of South Alabama) for providing the primary rat lung microvascular endothelial cells, J. Whitsett (University of Cincinnati) for allowing us to use the MLE-15 cells, T. Flotte and P. Cruz (Universities of Florida and Massachusetts, respectively) for preparing the AAV5 vectors, Y. Chen (University of Indiana) for the DDIT4 promoter constructs, I. Rahman (University of Rochester) for sharing cigarette smoke–sensitive and cigarette smoke–resistant mouse lung specimens, D. Brenner (University of California, San Diego) for the adenovirus IκB superrepressor, L. Ellison (Dana-Farber Cancer Center) for providing the DDIT4-RPAA construct and S. Reynolds (National Jewish Health) for the mouse-specific clara cell antigen 10 antibody. This work was supported by the grants R01 US National Heart, Lung, and Blood Institute (NHLBI) RO1 66554, Alpha 1 Foundation, Flight Attendant Medical Research Institute and Quark Pharmaceuticals (to R.M.T.); R01 NHLBI 077328 (to I.P.), COPD SCCOR P01–NHLBI 085609, Project 1 (to R.M.T. and I.P.) and Project 4 (to S.B.), RO1 NHLBI RO1 081205 to (S.B.) and NHLBI R01 HL082541–01 to (S.D.S.).
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T.Y., E.F. and R.M.T. designed the experiments, analyzed the data and composed the manuscript; T.Y., I.M., A.K.B., J.B., M.P., L. Zhang, A. Gandjeva, L. Zhen, U.C., T.M., A.R., E.B., H.A., N.N., A. Gelfand and I.P. performed in vitro and in vivo experiments; R.K.T., T.R., T.S. and S.B. provided mouse lung samples for Rtp801 expression studies; G.C. provided normal human lung samples for Rtp801 expression studies; M.M. and S.D.S. performed the chronic exposure to cigarette smoke.
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Yoshida, T., Mett, I., Bhunia, A. et al. Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke–induced pulmonary injury and emphysema. Nat Med 16, 767–773 (2010). https://doi.org/10.1038/nm.2157
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DOI: https://doi.org/10.1038/nm.2157