Pioglitazone attenuates alcohol-induced alveolar macrophage oxidative stress and dysfunction by up-regulating Nox4-associated microRNAs

Abstract

The lungs of individuals with alcohol use disorders (AUD) are the target organs for the injurious effects of combined alcohol and cigarette smoke metabolites. Malondialdehyde (MDA) and acetaldehyde (AA) exist in significant concentrations following the metabolism of ethanol and the pyrolysis of tobacco. Previously, it has been demonstrated that MDA and AA form a stable protein adduct, known as the malondialdehyde-acetaldehyde (MAA) adduct, which serves as the dominant epitope in the formation of anti-MAA antibodies under disease conditions of elevated MDA. In mouse lung, MAAadducted protein is detected only under conditions of alcohol and cigarette co-exposure where levels of MDA and AA are maximal. We hypothesized that lung MAA-adducted protein would lead to elevated anti-MAA antibodies in humans who have a significant exposure to cigarette smoke and alcohol. We performed bronchoalveolar lavage (BAL) on subjects with AUD and control subjects, a percentage of whom smoked. We utilized the Alcohol Use Disorders Identification Test (AUDIT) to identify patients with alcohol misuse to define an AUD. BAL cytospins were prepared and immunohistochemistry performed using rabbit anti-MAA adduct antibodies to quantitate BAL cells staining positive for MAA-adducts. Serum and BAL fluid were collected and assayed for the presence of anti-MAA antibody isotypes using an ELISA. Four subject groups were established and assayed: AUD subjects who smoked cigarettes (+AUD/+smoke), cigarette smokers without AUDs (� AUD/+smoke), AUD subjects who did not smoke cigarettes (+AUD/� smoke), and non-AUD/ non-cigarette smokers (� AUD/� smoke). A significant (p < 0.05) increase in the presence of MAA adducts was observed in the BAL cells of +AUD/+smoke vs. � AUD/� smoke (31.8 � 7.2 vs. 1.2 � 0.8, n