235 - Cigarette Smoke Induced Emphysema and Pulmonary Hypertension Are Triggered by Tobacco Smoke Oxidants: Attenuation by Vitamin C

Abstract

Cigarette smoking causes emphysema, a fatal disease involving extensive structural and functional damage of the lung followed by pulmonary hypertension that restricts pulmonary circulation and causes right ventricular dysfunction of the heart. 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 emphysematous lung injury, but are also responsible for the extensive pulmonary vascular remodelling that characterizes pulmonary hypertension. Tobacco-smoke oxidants activate the lung pro-inflammatory factor, Rtp801 which in turn stimulates nuclear-factor κB and consequent inducible nitric-oxide synthase (iNOS) mediated overproduction of nitric-oxide (NO) that contributes to lung protein nitration. However, lung-specific inhibition of iNOS with a iNOS-specific inhibitor, N6-​(1-​iminoethyl)-​L-​lysine,​ dihydrochloride (L-NIL) solely restricts the observed lung protein nitration but fails to prevent or reverse the major tobacco-smoke induced oxidative lung injury, contrary to recent reports (Cell;147(2):293-305, 2011). In fact, inhibition of pulmonary iNOS also significantly accelerates lung peri-vascular collagen deposition by up-regulating the expression of arginase I, a key enzyme associated with vascular remodelling and pulmonary hypertension. In comparison, the dietary antioxidant, ascorbate or vitamin C, can substantially prevent emphysematous lung damage by inhibiting both tobacco-smoke induced lung protein oxidation as well as activation of pulmonary Rtp801 and nitration of lung proteins, that otherwise lead to increased proteolysis of such oxidized or nitrated proteins by endogenous lung proteases, causing emphysema. 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 as well as arginase I, to prevent the subsequent peri-vascular collagen deposition and medial thickening of the pulmonary vessels causing pulmonary hypertension. Thus, our findings implicate tobacco-smoke oxidant(s) as the primary etiopathogenic factor behind both the emphysematous and vascular pathogenesis of the lung associated with smoking. More importantly, it demonstrates the potential of vitamin C to accomplish holistic prevention of both these major forms of tobacco-smoke induced lung damage Reference Proc. Natl. Acad. Sci, USA,113(29):E4208-17, 2016