Lipid Metabolic Changes and Mitochondrial Stress in Ethanol-Treated Alveolar Type II Epithelial Cells: Initial Events Leading to Alcoholic Chronic Lung Disease

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 22–130 mM EtOH for 6 h (concentration-dependent) and 65 mM EtOH for 6–72 h (time-dependent). Cytotoxicity, inflammation, surfactant lipid/protein dysregulation, fatty acid ethyl ester (FAEE) formation, cellular stress responses, AMP-activated protein kinase (AMPKα) signaling, and mitochondrial function were analyzed. EtOH disrupted surfactant homeostasis by reducing dipalmitoylphosphatidylcholine and surfactant protein C (SP-C). Importantly, EtOH inactivated AMPKα, downregulated CPT1A (involved in β-oxidation of fatty acids), and upregulated lipogenic proteins ACC1 and FAS, accompanied by increased ER stress markers (GRP78, p-eIF2α, 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 AMPKα-CPT1A signaling, and surfactant contribute to AT2 cell dysfunction and play a critical role in the pathogenesis of ARLD.