Role of nitric oxide and nitrosative protein damage in cigarette smoke-induced emphysematous lung damage: Attenuation by vitamin C

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Emphysema, is a common inflammatory lung disease caused by cigarette smoking involving extensive structural and functional damage of the lung, often causing death. Here, we demonstrate the role of the enzyme, nitric oxide synthase (NOS) and its biologically active product, nitric oxide (NO) in cigarette smoke-induced inflammatory lung damage using a guinea pig model of emphysema as well as human lung cells and deploying established immunoblotting, immunohistochemical and spectroscopic techniques. Our results indicate that cigarette smoke induces severe inflammatory changes in the lung, leading to over-expression of the inducible (iNOS) and endothelial (eNOS) isoforms of NOS as well as its product, NO, which reacts with superoxide ( O 2 ) to form peroxynitrite ( ONOO - - ) , triggering extensive nitration of lung proteins. Nitration renders lung proteins susceptible to proteolytic damage by endogenous proteases causing structural damage to the lung. Such proteolysis of nitrated proteins is also associated with increased apoptosis/necrosis of lung cells as well as lung alveolar airspace characteristic of emphysema. L-NIL, a specific iNOS inhibitor, arrested the observed protein nitration and lung damage indicating the predominant role of iNOS in such nitrosative lung damage. We also found that vitamin C, a potent dietary antioxidant can attenuate the observed cigarette smoke-induced nitrosative lung damage by scavenging the responsible NO, O 2 and ONOO− species. Overall, our work indicates the predominant role of iNOS and NO in the inflammatory lung damage implicated with cigarette smoke-induced emphysema and the potential of vitamin C to attenuate such damage. We will use this new mouse model to investigate the role of BH4-dependent and independent NOS functions in models of vascular function, disease and inflammation.