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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 ofmore » 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. - Highlights: • Chronic ethanol feeding causes oxidative stress, ER stress and inflammation in lungs of ADH– deer mice. • Chronic ethanol feeding generates FAEEs (nonoxidative metabolites of ethanol) in lungs of ADH– deer mice. • Chronic ethanol feeding induces CYP2E1 in the lungs of ADH– deer mice. • Lack of ER homeostasis due to a prolonged ethanol feeding could trigger inflammation.« less

Authors:
 [1];  [2];  [3];  [1]
  1. Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 775555 (United States)
  2. Department of Pathology, The University of Texas Medical Branch, Galveston, TX 775555 (United States)
  3. Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, TX 775555 (United States)
Publication Date:
OSTI Identifier:
22439721
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 277; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACETALDEHYDE; ALCOHOL DEHYDROGENASE; BIOLOGICAL PATHWAYS; BLOOD; CARBOXYLIC ACIDS; CONCENTRATION RATIO; ENDOPLASMIC RETICULUM; ETHANOL; FEEDING; HOMEOSTASIS; INFLAMMATION; INJURIES; LIVER; LUNGS; METABOLISM; MICE; OXIDATION; PATHOGENESIS; STRESSES

Citation Formats

Kaphalia, Lata, Boroumand, Nahal, Hyunsu, Ju, Kaphalia, Bhupendra S., E-mail: bkaphali@utmb.edu, and Calhoun, William J. Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress responses in the lungs of hepatic alcohol dehydrogenase deficient deer mice after chronic ethanol feeding. United States: N. p., 2014. Web. doi:10.1016/J.TAAP.2014.02.018.
Kaphalia, Lata, Boroumand, Nahal, Hyunsu, Ju, Kaphalia, Bhupendra S., E-mail: bkaphali@utmb.edu, & Calhoun, William J. Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress responses in the lungs of hepatic alcohol dehydrogenase deficient deer mice after chronic ethanol feeding. United States. https://doi.org/10.1016/J.TAAP.2014.02.018
Kaphalia, Lata, Boroumand, Nahal, Hyunsu, Ju, Kaphalia, Bhupendra S., E-mail: bkaphali@utmb.edu, and Calhoun, William J. 2014. "Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress responses in the lungs of hepatic alcohol dehydrogenase deficient deer mice after chronic ethanol feeding". United States. https://doi.org/10.1016/J.TAAP.2014.02.018.
@article{osti_22439721,
title = {Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress responses in the lungs of hepatic alcohol dehydrogenase deficient deer mice after chronic ethanol feeding},
author = {Kaphalia, Lata and Boroumand, Nahal and Hyunsu, Ju and Kaphalia, Bhupendra S., E-mail: bkaphali@utmb.edu and Calhoun, William J.},
abstractNote = {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. - Highlights: • Chronic ethanol feeding causes oxidative stress, ER stress and inflammation in lungs of ADH– deer mice. • Chronic ethanol feeding generates FAEEs (nonoxidative metabolites of ethanol) in lungs of ADH– deer mice. • Chronic ethanol feeding induces CYP2E1 in the lungs of ADH– deer mice. • Lack of ER homeostasis due to a prolonged ethanol feeding could trigger inflammation.},
doi = {10.1016/J.TAAP.2014.02.018},
url = {https://www.osti.gov/biblio/22439721}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 2,
volume = 277,
place = {United States},
year = {Sun Jun 01 00:00:00 EDT 2014},
month = {Sun Jun 01 00:00:00 EDT 2014}
}