| First Author | Yeligar SM | Year | 2016 |
| Journal | Am J Respir Cell Mol Biol | Volume | 55 |
| Issue | 1 | Pages | 35-46 |
| PubMed ID | 26677910 | Mgi Jnum | J:251045 |
| Mgi Id | MGI:6101281 | Doi | 10.1165/rcmb.2015-0077OC |
| Citation | Yeligar SM, et al. (2016) Peroxisome Proliferator-Activated Receptor gamma Regulates Chronic Alcohol-Induced Alveolar Macrophage Dysfunction. Am J Respir Cell Mol Biol 55(1):35-46 |
| abstractText | Peroxisome proliferator-activated receptor (PPAR) gamma is critical for alveolar macrophage (AM) function. Chronic alcohol abuse causes AM phagocytic dysfunction and susceptibility to respiratory infections by stimulating nicotinamide adenine dinucleotide oxidases (Nox), transforming growth factor-beta1, and oxidative stress in the AM. Because PPARgamma inhibits Nox expression, we hypothesized that alcohol reduces PPARgamma, stimulating AM dysfunction. AMs were examined from: (1) patients with alcoholism or control patients; (2) a mouse model of chronic ethanol consumption; (3) PPARgamma knockout mice; or (4) MH-S cells exposed to ethanol in vitro. Alcohol reduced AM PPARgamma levels and increased Nox1, -2, and -4, transforming growth factor-beta1, oxidative stress, and phagocytic dysfunction. Genetic loss of PPARgamma recapitulated, whereas stimulating PPARgamma activity attenuated alcohol-mediated alterations in gene expression and phagocytic function, supporting the importance of PPARgamma in alcohol-induced AM derangements. Similarly, PPARgamma activation in vivo reduced alcohol-mediated impairments in lung bacterial clearance. Alcohol increased levels of microRNA-130a/-301a, which bind to the PPARgamma 3'' untranslated region to reduce PPARgamma expression. MicroRNA-130a/-301a inhibition attenuated alcohol-mediated PPARgamma reductions and derangements in AM gene expression and function. Alcohol-induced Toll-like receptor 4 endocytosis was reversed by PPARgamma activation. These findings demonstrate that targeting PPARgamma provides a novel therapeutic approach for mitigating alcohol-induced AM derangements and susceptibility to lung infection. |
