{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T05:22:21Z","timestamp":1763702541226,"version":"3.45.0"},"reference-count":86,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health","award":["AA24699","AA25850","AA030883"],"award-info":[{"award-number":["AA24699","AA25850","AA030883"]}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"crossref","award":["RP190682"],"award-info":[{"award-number":["RP190682"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Alcohol use disorder (AUD) predisposes individuals to pneumonia, acute respiratory distress syndrome, and chronic obstructive pulmonary disease, yet the mechanisms underlying alcohol-related lung disease (ARLD) remain unclear. Alveolar type II (AT2) epithelial cells play a central role in ethanol (EtOH) metabolism, surfactant production, alveolar repair, and pulmonary innate immunity. To examine EtOH-mediated effects, immortalized human AT2 cells were treated with 22\u2013130 mM EtOH for 6 h (concentration-dependent) and 65 mM EtOH for 6\u201372 h (time-dependent). Cytotoxicity, inflammation, surfactant lipid\/protein dysregulation, fatty acid ethyl ester (FAEE) formation, cellular stress responses, AMP-activated protein kinase (AMPK\u03b1) signaling, and mitochondrial function were analyzed. EtOH disrupted surfactant homeostasis by reducing dipalmitoylphosphatidylcholine and surfactant protein C (SP-C). Importantly, EtOH inactivated AMPK\u03b1, downregulated CPT1A (involved in \u03b2-oxidation of fatty acids), and upregulated lipogenic proteins ACC1 and FAS, accompanied by increased ER stress markers (GRP78, p-eIF2\u03b1, and CHOP). Expression of carboxyl ester lipase (FAEE-synthesizing enzyme) and FAEE levels increased with EtOH exposure, further exacerbating oxidative and ER stress, impairing mitochondrial energetics, ATP production, and AT2 cell function. These findings suggest that EtOH-induced FAEE formation, dysregulation of AMPK\u03b1-CPT1A signaling, and surfactant contribute to AT2 cell dysfunction and play a critical role in the pathogenesis of ARLD.<\/jats:p>","DOI":"10.3390\/cells14221817","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T15:03:15Z","timestamp":1763564595000},"page":"1817","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lipid Metabolic Changes and Mitochondrial Stress in Ethanol-Treated Alveolar Type II Epithelial Cells: Initial Events Leading to Alcoholic Chronic Lung Disease"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3307-2305","authenticated-orcid":false,"given":"Mukund","family":"Srinivasan","sequence":"first","affiliation":[{"name":"Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77550, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bhupendra S.","family":"Kaphalia","sequence":"additional","affiliation":[{"name":"Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77550, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e73","DOI":"10.1016\/j.amepre.2015.05.031","article-title":"2010 National and State Costs of Excessive Alcohol Consumption","volume":"49","author":"Sacks","year":"2015","journal-title":"Am. 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