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Division of Cardiopulmonary Pathology, Department of Pathology, and Division of Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine; Division of Toxicological Sciences, Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; and Quark Biotech, Inc., Fremont, California
Correspondence and requests for reprints should be addressed to Rubin M. Tuder, M.D., Division of Cardiopulmonary Pathology, Department of Pathology, School of Medicine, Johns Hopkins University, Ross Research Building, 519, 720 Rutland Avenue, Baltimore, MD 21205. E-mail: rtuder{at}jhmi.edu
RTP801/REDD1/dig2 is expressed under the conditions of multiple stresses through hypoxia-inducible factor-1
–dependent or –independent manner and suppresses the mammalian target of rapamycin (mTOR)-mediated signal transduction to control cell growth and protein synthesis. Intravenous systemic delivery of plasmid DNA encoding hRTP801 to mice is efficient in causing massive apoptosis of alveolar wall cells. We hypothesized that, as part of an overall lung response to cellular stress, cigarette smoke (CS) activates RTP801, thus leading to enhanced apoptosis in alveolar wall cells. CS exposure resulted in greatly increased expression of RTP801 protein in the lung of both C57BL/6 mice and heterozygous 129/SvEv x C57BL/6 mice. The immunopositive reaction was more evident in alveolar wall cells than in alveolar macrophages. After 7-d CS exposure, RTP801 knockout mice showed significantly lower numbers of bronchoalveolar lavage leukocytes, pulmonary neutrophils, and alveolar wall apoptotic (active caspase-3–positive) cells when compared with wild-type mice. C57BL/6 mice exposed to CS and intranasally instilled RTP801 siRNA also showed decreased bronchoalveolar lavage leukocytes and alveolar wall apoptotic cells when compared with control siRNA-instilled mice. In contrast, C57BL/6 mice with intratracheal instillation of plasmid DNA encoding hRTP801 significantly increased active caspase-3 as compared with the mice instilled with control plasmid DNA. Moreover, a limited assessment of human lung samples demonstrated that RTP801 protein was likely higher expressed in emphysematous lungs than in controls. These results suggest that RTP801 may be a signaling molecule involved in pulmonary injury in mice exposed to CS and also relevant to human emphysema, thus revealing the potential participation of a novel signaling pathway in these diseases.
FOOTNOTES
Conflict of Interest Statement: T.Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. I.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. I.M. is an employee of Quark Biotech, Inc., a company that sponsored the study, and owns patent application on the matter. His institution is a commercial entity. E.F. is an employee of Quark Biotech, Inc., which sponsored the study, and owns patent application on the matter. Her institution is a commercial entity. R.M.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form March 20, 2006; accepted in final form March 28, 2006)
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