title: Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress responses in the lungs of hepatic alcohol dehydrogenase deficient deer mice after chronic ethanol feeding.
abstract: Consumption and over-consumption of alcoholic beverages are well-recognized contributors to a variety of pulmonary disorders, even in the absence of intoxication. The mechanisms by which alcohol (ethanol) may produce disease include oxidative stress and prolonged endoplasmic reticulum (ER) stress. Many aspects of these processes remain incompletely understood due to a lack of a suitable animal model. Chronic alcohol over-consumption reduces hepatic alcohol dehydrogenase (ADH), the principal canonical metabolic pathway of ethanol oxidation. We therefore modeled this situation using hepatic ADH-deficient deer mice fed 3.5% ethanol daily for 3 months. Blood ethanol concentration was 180 mg% in ethanol fed mice, compared to <1.0% in the controls. Acetaldehyde (oxidative metabolite of ethanol) was minimally, but significantly increased in ethanol-fed vs. pair-fed control mice. Total fatty acid ethyl esters (FAEEs, nonoxidative metabolites of ethanol) were 47.6 μg/g in the lungs of ethanol-fed mice as compared to 1.5 μg/g in pair-fed controls. Histological and immunohistological evaluation showed perivascular and peribronchiolar lymphocytic infiltration, and significant oxidative injury, in the lungs of ethanol-fed mice compared to pair-fed controls. Several fold increases for cytochrome P450 2E1, caspase 8 and caspase 3 found in the lungs of ethanol-fed mice as compared to pair-fed controls suggest role of oxidative stress in ethanol-induced lung injury. ER stress and unfolded protein response signaling were also significantly increased in the lungs of ethanol-fed mice. Surprisingly, no significant activation of inositol-requiring enzyme-1α and spliced XBP1 was observed indicating a lack of activation of corrective mechanisms to reinstate ER homeostasis. The data suggest that oxidative stress and prolonged ER stress, coupled with formation and accumulation of cytotoxic FAEEs may contribute to the pathogenesis of alcoholic lung disease.
authors.affiliation: Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 775555, USA.
authors.forename: Lata
authors.initials: L
authors.lastname: Kaphalia
authors.affiliation: Department of Pathology, The University of Texas Medical Branch, Galveston, TX 775555, USA.
authors.forename: Nahal
authors.initials: N
authors.lastname: Boroumand
authors.affiliation: Department of Preventive Medicine & Community Health, The University of Texas Medical Branch, Galveston, TX 775555, USA.
authors.forename: Ju
authors.initials: J
authors.lastname: Hyunsu
authors.affiliation: Department of Pathology, The University of Texas Medical Branch, Galveston, TX 775555, USA. Electronic address: bkaphali@utmb.edu.
authors.forename: Bhupendra S
authors.initials: BS
authors.lastname: Kaphalia
authors.affiliation: Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 775555, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Calhoun
mesh_terms: D000079:Acetaldehyde / Q000097:blood; D000426:Alcohol Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D000428:Alcohol Drinking / Q000009:adverse effects* / Q000097:blood / Q000473:pathology; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004951:Esterification; D004952:Esters / Q000378:metabolism; D000431:Ethanol / Q000097:blood / Q000633:toxicity*; D005227:Fatty Acids / Q000378:metabolism; D005838:Genotype; D008099:Liver / Q000201:enzymology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D010542:Peromyscus; D010641:Phenotype; D013997:Time Factors; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D004952:Esters; D005227:Fatty Acids; D000431:Ethanol; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D053148:Caspase 3; D053181:Caspase 8; D000079:Acetaldehyde
keywords: Alcoholic lung injury; ER stress; Ethanol; Fatty acid ethyl esters; Oxidative stress; Unfolded protein responses