title: Chronic alcohol ingestion in rats alters lung metabolism, promotes lipid accumulation, and impairs alveolar macrophage functions.
abstract: Chronic alcoholism impairs pulmonary immune homeostasis and predisposes to inflammatory lung diseases, including infectious pneumonia and acute respiratory distress syndrome. Although alcoholism has been shown to alter hepatic metabolism, leading to lipid accumulation, hepatitis, and, eventually, cirrhosis, the effects of alcohol on pulmonary metabolism remain largely unknown. Because both the lung and the liver actively engage in lipid synthesis, we hypothesized that chronic alcoholism would impair pulmonary metabolic homeostasis in ways similar to its effects in the liver. We reasoned that perturbations in lipid metabolism might contribute to the impaired pulmonary immunity observed in people who chronically consume alcohol. We studied the metabolic consequences of chronic alcohol consumption in rat lungs in vivo and in alveolar epithelial type II cells and alveolar macrophages (AMs) in vitro. We found that chronic alcohol ingestion significantly alters lung metabolic homeostasis, inhibiting AMP-activated protein kinase, increasing lipid synthesis, and suppressing the expression of genes essential to metabolizing fatty acids (FAs). Furthermore, we show that these metabolic alterations promoted a lung phenotype that is reminiscent of alcoholic fatty liver and is characterized by marked accumulation of triglycerides and free FAs within distal airspaces, AMs, and, to a lesser extent, alveolar epithelial type II cells. We provide evidence that the metabolic alterations in alcohol-exposed rats are mechanistically linked to immune impairments in the alcoholic lung: the elevations in FAs alter AM phenotypes and suppress both phagocytic functions and agonist-induced inflammatory responses. In summary, our work demonstrates that chronic alcohol ingestion impairs lung metabolic homeostasis and promotes pulmonary immune dysfunction. These findings suggest that therapies aimed at reversing alcohol-related metabolic alterations might be effective for preventing and/or treating alcohol-related pulmonary disorders.
authors.affiliation: 1 Center for Translational Medicine.
authors.forename: Freddy
authors.initials: F
authors.lastname: Romero
authors.forename: Dilip
authors.initials: D
authors.lastname: Shah
authors.forename: Michelle
authors.initials: M
authors.lastname: Duong
authors.forename: William
authors.initials: W
authors.lastname: Stafstrom
authors.forename: Jan B
authors.initials: JB
authors.lastname: Hoek
authors.forename: Caleb B
authors.initials: CB
authors.lastname: Kallen
authors.forename: Charles H
authors.initials: CH
authors.lastname: Lang
authors.forename: Ross
authors.initials: R
authors.lastname: Summer
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000428:Alcohol Drinking / Q000009:adverse effects*; D000818:Animals; D016764:Cell Polarity; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004789:Enzyme Activation; D000431:Ethanol / Q000494:pharmacology; D050155:Lipogenesis / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010587:Phagocytosis; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D014280:Triglycerides; D000431:Ethanol; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D000263:Adenylate Kinase
keywords: AMP-activated protein kinase; chronic alcohol ingestion; macrophage; surfactant lipids