title: Ascorbate attenuates pulmonary emphysema by inhibiting tobacco smoke and Rtp801-triggered lung protein modification and proteolysis.
abstract: Cigarette smoking causes emphysema, a fatal disease involving extensive structural and functional damage of the lung. Using a guinea pig model and human lung cells, we show that oxidant(s) present in tobacco smoke not only cause direct oxidative damage of lung proteins, contributing to the major share of lung injury, but also activate Rtp801, a key proinflammatory cellular factor involved in tobacco smoke-induced lung damage. Rtp801 triggers nuclear factor κB and consequent inducible NOS (iNOS)-mediated overproduction of NO, which in combination with excess superoxide produced during Rtp801 activation, contribute to increased oxido-nitrosative stress and lung protein nitration. However, lung-specific inhibition of iNOS with a iNOS-specific inhibitor, N6-(1-iminoethyl)-L-lysine, dihydrochloride (L-NIL) solely restricts lung protein nitration but fails to prevent or reverse the major tobacco smoke-induced oxidative lung injury. In comparison, the dietary antioxidant, ascorbate or vitamin C, can substantially prevent such damage by inhibiting both tobacco smoke-induced lung protein oxidation as well as activation of pulmonary Rtp801 and consequent iNOS/NO-induced nitration of lung proteins, that otherwise lead to increased proteolysis of such oxidized or nitrated proteins by endogenous lung proteases, resulting in emphysematous lung damage. Vitamin C also restricts the up-regulation of matrix-metalloproteinase-9, the major lung protease involved in the proteolysis of such modified lung proteins during tobacco smoke-induced emphysema. Overall, our findings implicate tobacco-smoke oxidant(s) as the primary etiopathogenic factor behind both the noncellular and cellular damage mechanisms governing emphysematous lung injury and demonstrate the potential of vitamin C to accomplish holistic prevention of such damage.
authors.affiliation: Department of Biotechnology and Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, Kolkata 700019, India;
authors.forename: Indranil
authors.initials: I
authors.lastname: Gupta
authors.affiliation: Department of Biotechnology and Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, Kolkata 700019, India;
authors.forename: Souradipta
authors.initials: S
authors.lastname: Ganguly
authors.affiliation: Proteomics Applications Laboratory, GE Healthcare Life Sciences, Piscataway, NJ 08854;
authors.forename: Christine R
authors.initials: CR
authors.lastname: Rozanas
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Stuehr
authors.affiliation: Department of Biotechnology and Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, Kolkata 700019, India; pandak66@yahoo.co.uk.
authors.forename: Koustubh
authors.identifier: 0000-0002-4783-2221
authors.initials: K
authors.lastname: Panda
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001205:Ascorbic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007958:Leukocyte Count; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D011656:Pulmonary Emphysema / Q000188:drug therapy* / Q000378:metabolism*; D012906:Smoke / Q000009:adverse effects*; D014157:Transcription Factors / Q000378:metabolism; D014026:Nicotiana
chemical_list: D000975:Antioxidants; D016207:Cytokines; C469991:DDIT4 protein, human; D012906:Smoke; D014157:Transcription Factors; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D001205:Ascorbic Acid
keywords: Rtp801; ascorbate; cigarette smoke; emphysema; vitamin C