title: Chronic alcohol ingestion exacerbates lung epithelial barrier dysfunction in HIV-1 transgenic rats.
abstract: BACKGROUND
  Alcohol abuse and HIV-1 infection frequently coexist, and these individuals are at high risk for serious lung infections and respiratory failure. Although alcohol ingestion and HIV-1 transgene expression have been shown to independently cause oxidative stress and disrupt alveolar epithelial barrier function in experimental models, their interactive effects have not been examined.
  
  
  RESULTS
  In this study, we determined that chronic alcohol ingestion (12 weeks) exacerbated the already significant defects in alveolar epithelial paracellular permeability and lung liquid clearance in HIV-1 transgenic rats. Further, immunocytochemical analyses of tight junction protein expression in primary alveolar epithelial cells showed that occludin and zonula occludens-1 localization within the plasma membrane was more disrupted than in either condition alone, consistent with the observed defects in epithelial barrier function. Interestingly, expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), the transcription factor required to activate the antioxidant-response element, was decreased in primary alveolar epithelial cells isolated from HIV-1 transgenic rats. In parallel, exposing lung epithelial cells in vitro to either alcohol or the HIV-related protein gp120 also decreased Nrf2 expression. Importantly, treatment with procysteine, which increases thiol antioxidants including glutathione, improved tight junction protein localization in the plasma membrane and restored alveolar epithelial barrier function in alcohol-fed HIV-1 transgenic rats.
  
  
  CONCLUSIONS
  These results provide novel evidence that HIV-related proteins and alcohol together causes more barrier dysfunction in the lung epithelium than either stress alone. However, these significant effects on the alveolar barrier can be mitigated by augmenting the thiol antioxidant pool, a strategy with potential clinical applications in subjects who are highly vulnerable to lung disease because of coexistent alcohol abuse and HIV infection.
authors.affiliation: Pulmonary Section, Atlanta VAMC, Atlanta, Georgia, USA. xfan@emory.edu
authors.forename: Xian
authors.initials: X
authors.lastname: Fan
authors.forename: Pratibha C
authors.initials: PC
authors.lastname: Joshi
authors.forename: Michael
authors.initials: M
authors.lastname: Koval
authors.forename: David M
authors.initials: DM
authors.lastname: Guidot
mesh_terms: D000437:Alcoholism / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000975:Antioxidants / Q000502:physiology; D002492:Central Nervous System Depressants / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D015897:Comorbidity; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004847:Epithelial Cells / Q000473:pathology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015658:HIV Infections / Q000378:metabolism / Q000473:pathology*; D015497:HIV-1; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008171:Lung Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000378:metabolism; D062793:Occludin; D011761:Pyrrolidonecarboxylic Acid / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D053778:Thiazolidines / Q000494:pharmacology; D019108:Tight Junctions / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D000975:Antioxidants; D002492:Central Nervous System Depressants; D015699:HIV Envelope Protein gp120; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C568985:OCLN protein, human; D062793:Occludin; C568987:Ocln protein, rat; D053778:Thiazolidines; C514793:gp120 protein, Human immunodeficiency virus 1; D000431:Ethanol; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid