Several conditions are marked by increased susceptibility to, and enhanced severity of, bacterial infections. Alcohol use disorder, one of these conditions, is known to predispose to bacterial pneumonia by suppressing the lung's innate immune system, and more specifically by disrupting critical alveolar macrophage (AM) functions. Recently, we established that chronic ethanol consumption also perturbs surfactant lipid homeostasis in the lung and that elevated concentrations of free fatty acids contribute to blocking essential AM functions, such as agonist-induced cytokine expression. In this study, we extend these observations by showing that elevated free fatty acid levels impair metabolic responses to lipopolysaccharide (LPS) in AMs. In particular, we show that the glycolytic reprogramming characteristic of LPS-stimulated AMs is blunted by the saturated fatty acid palmitate, whereas oleate, an unsaturated fatty acid, or ethanol alone, had no effect on this adaptive metabolic response. Additionally, we found that elevated concentrations of palmitate induced mitochondrial oxidative stress and that glycolytic reprogramming and cytokine production to LPS could be partially restored in AMs by either pharmacologically blocking palmitate entry into mitochondria or administering a mitochondrial-specific antioxidant. Taken together, these findings suggest that alcohol and elevated levels of saturated fatty acids conspire to impair pulmonary innate immunity by altering metabolic responses in AMs. Additionally, our findings suggest that targeting the mechanisms involved in fatty acid metabolism can restore pulmonary immunity and possibly limit bacterial pneumonia in individuals with alcohol use disorder.

中文翻译：

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酒精引起的脂质失调损害了肺泡巨噬细胞对LPS的糖酵解反应。

对细菌感染的易感性和严重性的增加标志着几种疾病。已知这些病症之一的酒精使用障碍会通过抑制肺的先天免疫系统，更具体地通过破坏关键的肺泡巨噬细胞（AM）功能而诱发细菌性肺炎。最近，我们确定了长期的乙醇消耗也会扰乱肺中的表面活性剂脂质稳态，并且升高的游离脂肪酸浓度有助于阻断​​基本的AM功能，例如激动剂诱导的细胞因子表达。在这项研究中，我们通过显示升高的游离脂肪酸水平削弱了AM中对脂多糖（LPS）的代谢反应，扩展了这些观察结果。特别是，我们表明，LPS刺激的AMs的糖酵解重编程特性受饱和脂肪酸棕榈酸酯的影响，而油酸酯，不饱和脂肪酸或单独的乙醇对这种适应性代谢反应没有影响。此外，我们发现，通过药理学上阻止棕榈酸酯进入线粒体或施用线粒体特异性抗氧化剂，可以在AM中部分恢复高浓度的棕榈酸酯诱导的线粒体氧化应激以及糖酵解重编程和向LPS的细胞因子产生。综上所述，这些发现表明，酒精和饱和脂肪酸水平的升高共同通过改变AMs的代谢反应而削弱了肺的先天免疫力。另外，