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Ethanol Exposure Impairs AMPK Signaling and Phagocytosis in Human Alveolar Macrophages: Role of Ethanol Metabolism
Author(s) -
Kaphalia Lata,
Srinivasan Mukund P.,
Kakumanu Ramu D.,
Kaphalia Bhupendra S.,
Calhoun William J.
Publication year - 2019
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.14131
Subject(s) - oxidative stress , chemistry , ampk , oxidative phosphorylation , phagocytosis , endocrinology , biochemistry , medicine , protein kinase a , phosphorylation , biology , microbiology and biotechnology
Background Chronic alcohol consumption impairs alveolar macrophage's (AM) function and increases risk for developing lung infection and pneumonia. However, the mechanism and metabolic basis of alcohol‐induced AM dysfunction leading to lung infection are not well defined, but may include altered ethanol (EtOH) and reactive oxygen species metabolism and cellular energetics. Therefore, oxidative stress, endoplasmic reticulum (ER) stress, the formation of fatty acid ethyl esters [FAEEs, nonoxidative metabolites of EtOH], AMP‐activated protein kinase (AMPK) signaling, and phagocytic function were examined in freshly isolated AM incubated with EtOH. Methods AMs separated from bronchoalveolar lavage fluid samples obtained from normal volunteers were incubated with EtOH for 24 hours. AMPK signaling and ER stress were assessed using Western blotting, FAEEs by GC‐MS, oxidative stress by immunofluorescence using antibodies to 4‐hydroxynonenal, and phagocytosis by latex beads. Oxidative stress was also measured in EtOH‐treated AMs with/without AMPK activator [5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR)] or inhibitor (Compound C), and in AMs incubated with FAEEs. mRNA expression for interleukins (IL‐6 and IL‐8), monocyte chemoattractant protein (MCP)‐1, and transforming growth factor (TGF)‐β was measured in AM treated with EtOH or FAEEs using RT‐PCR. Results EtOH exposure to AM increased oxidative stress, ER stress, and synthesis of FAEEs, decreased phosphorylated AMPK, and impaired phagocytosis. Attenuation or exacerbation of EtOH‐induced oxidative stress by AICAR or Compound C, respectively, suggests a link between AMPK signaling, EtOH metabolism, and related oxidative stress. The formation of FAEEs may contribute to EtOH‐induced oxidative stress as FAEEs also produced concentration‐dependent oxidative stress. An increased mRNA expression of IL‐6, IL‐8, and MCP‐1 by FAEEs is key finding to suggest a metabolic basis of EtOH‐induced inflammatory response. Conclusions EtOH‐induced impaired phagocytosis, oxidative stress, ER stress, and dysregulated AMPK signaling are plausibly associated with the formation of FAEEs and may participate in the pathogenesis of nonspecific pulmonary inflammation.