Aging Adversely Affects the Cigarette Smoke-induced Glutathione Adaptive Response in the Lung

Rationale: Cigarette smoke (CS) is the leading cause of chronic obstructive pulmonary disease, accounting for more than 90% of cases. The prevalence of chronic obstructive pulmonary disease is much higher in the elderly, suggesting an age dependency. A prominent defense against the oxidant burden caused by CS is the glutathione (GSH) adaptive response in the lung epithelial lining fluid (ELF) and tissue. However, as one ages the ability to maintain GSH levels declines. Objectives: Examine the effect of aging on the GSH adaptive response to CS and resulting lung sensitization to inflammation and oxidation. Methods: Both young (2 mo old) and aged (8, 13, 19, and 26 mo old) mice were used to study the effects of age on the GSH adaptive response after an acute exposure to CS. Measurements and Main Results: Young mice had a robust sixfold increase in ELF GSH after a single exposure to CS. The GSH response to CS decreased as a function of age and diminishes in the older mice to only a twofold increase over air controls. As a consequence, levels of CS-induced tumor necrosis factor-alpha and nitric oxide synthase, markers of inflammation, and 8-hydroxy-2-deoxyguanosine, a marker of DNA oxidation, were elevated in the aged mice compared with the young mice. Additionally, depletion of ELF GSH with buthionine sulfoximine in young mice recapitulated changes in ELF tumor necrosis factor-alpha as seen in old mice. Conclusions: These data suggest that the age-related maladaptive response to CS sensitizes the lung to both inflammation and oxidation potentially contributing to the development of CS-induced chronic obstructive pulmonary disease.