Romero Freddy, Shah Dilip, Duong Michelle, Stafstrom William, Hoek Jan B, Kallen Caleb B, Lang Charles H, Summer Ross
1 Center for Translational Medicine.
Am J Respir Cell Mol Biol. 2014 Dec;51(6):840-9. doi: 10.1165/rcmb.2014-0127OC.
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.
慢性酒精中毒会损害肺部免疫稳态，使人易患炎症性肺病，包括感染性肺炎和急性呼吸窘迫综合征。尽管酒精中毒已被证明会改变肝脏代谢，导致脂质蓄积、肝炎，并最终发展为肝硬化，但酒精对肺部代谢的影响仍 largely unknown。由于肺和肝脏都积极参与脂质合成，我们推测慢性酒精中毒会以类似于其对肝脏影响的方式损害肺部代谢稳态。我们推断脂质代谢紊乱可能是导致长期饮酒者肺部免疫受损的原因。我们研究了慢性酒精摄入对大鼠肺组织在体内以及对体外肺泡II型上皮细胞和肺泡巨噬细胞（AMs）的代谢影响。我们发现慢性酒精摄入会显著改变肺代谢稳态，抑制AMP激活的蛋白激酶，增加脂质合成，并抑制脂肪酸（FAs）代谢所必需基因的表达。此外，我们表明这些代谢改变促使肺部出现一种类似于酒精性脂肪肝的表型，其特征是在远端气腔、AMs以及程度较轻的肺泡II型上皮细胞内显著积累甘油三酯和游离FAs。我们提供的证据表明，酒精暴露大鼠的代谢改变与酒精性肺中的免疫损伤存在机制上的联系：FAs升高会改变AMs表型，并抑制吞噬功能和激动剂诱导的炎症反应。总之，我们的研究表明慢性酒精摄入会损害肺代谢稳态并促进肺部免疫功能障碍。这些发现表明，旨在逆转与酒精相关的代谢改变的疗法可能对预防和/或治疗与酒精相关的肺部疾病有效。
