title: Peroxisome Proliferator-Activated Receptor γ Regulates Chronic Alcohol-Induced Alveolar Macrophage Dysfunction.
abstract: Peroxisome proliferator-activated receptor (PPAR) γ 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-β1, and oxidative stress in the AM. Because PPARγ inhibits Nox expression, we hypothesized that alcohol reduces PPARγ, stimulating AM dysfunction. AMs were examined from: (1) patients with alcoholism or control patients; (2) a mouse model of chronic ethanol consumption; (3) PPARγ knockout mice; or (4) MH-S cells exposed to ethanol in vitro. Alcohol reduced AM PPARγ levels and increased Nox1, -2, and -4, transforming growth factor-β1, oxidative stress, and phagocytic dysfunction. Genetic loss of PPARγ recapitulated, whereas stimulating PPARγ activity attenuated alcohol-mediated alterations in gene expression and phagocytic function, supporting the importance of PPARγ in alcohol-induced AM derangements. Similarly, PPARγ activation in vivo reduced alcohol-mediated impairments in lung bacterial clearance. Alcohol increased levels of microRNA-130a/-301a, which bind to the PPARγ 3' untranslated region to reduce PPARγ expression. MicroRNA-130a/-301a inhibition attenuated alcohol-mediated PPARγ reductions and derangements in AM gene expression and function. Alcohol-induced Toll-like receptor 4 endocytosis was reversed by PPARγ activation. These findings demonstrate that targeting PPARγ provides a novel therapeutic approach for mitigating alcohol-induced AM derangements and susceptibility to lung infection.
authors.affiliation: 1 Emory University, Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Emory and Children's Healthcare of Atlanta Center for Developmental Lung Biology, Atlanta, Georgia.|2 Emory University, Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Decatur, Georgia.
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Yeligar
authors.affiliation: 2 Emory University, Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Decatur, Georgia.
authors.forename: Ashish J
authors.initials: AJ
authors.lastname: Mehta
authors.affiliation: 1 Emory University, Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Emory and Children's Healthcare of Atlanta Center for Developmental Lung Biology, Atlanta, Georgia.
authors.forename: Frank L
authors.initials: FL
authors.lastname: Harris
authors.affiliation: 1 Emory University, Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Emory and Children's Healthcare of Atlanta Center for Developmental Lung Biology, Atlanta, Georgia.
authors.forename: Lou Ann S
authors.initials: LA
authors.lastname: Brown
authors.affiliation: 2 Emory University, Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Atlanta Veterans Affairs and Emory University Medical Centers, Decatur, Georgia.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Hart
mesh_terms: D000818:Animals; D002460:Cell Line; D000431:Ethanol / Q000009:adverse effects*; D006801:Humans; D007709:Klebsiella / Q000187:drug effects; D008024:Ligands; D008168:Lung / Q000382:microbiology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism*; D010586:Phagocytes / Q000187:drug effects / Q000473:pathology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D008024:Ligands; C554019:MIRN130 microRNA, human; C550735:MIRN301A microRNA, human; D035683:MicroRNAs; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000431:Ethanol
keywords: alcohol; alveolar macrophage; bacterial clearance; microRNA; phagocytosis