Abstract
BackgroundHIV-infected individuals are at increased risk for acute and chronic airway disease even though there is no evidence that the virus can infect the lung epithelium. Although HIV-related proteins including gp120 and Tat can directly cause oxidant stress and cellular dysfunction, their effects in the lung are unknown. The goal of this study was to determine the effects of HIV-1 transgene expression in rats on alveolar epithelial barrier function. Alveolar epithelial barrier function was assessed by determining lung liquid clearance in vivo and alveolar epithelial monolayer permeability in vitro. Oxidant stress in the alveolar space was determined by measuring the glutathione redox couple by high performance liquid chromatography, and the expression and membrane localization of key tight junction proteins were assessed. Finally, the direct effects of the HIV-related proteins gp120 and Tat on alveolar epithelial barrier formation and tight junction protein expression were determined.ResultsHIV-1 transgene expression caused oxidant stress within the alveolar space and impaired epithelial barrier function even though there was no evidence of overt inflammation within the airways. The expression and membrane localization of the tight junction proteins zonula occludens-1 and occludin were decreased in alveolar epithelial cells from HIV-1 transgenic rats. Further, treating alveolar epithelial monolayers from wild type rats in vitro with recombinant gp120 or Tat for 24 hours reproduced many of the effects on zonula occludens-1 and occludin expression and membrane localization.ConclusionTaken together, these data indicate that HIV-related proteins cause oxidant stress and alter the expression of critical tight junction proteins in the alveolar epithelium, resulting in barrier dysfunction.
Highlights
human immunodeficiency virus (HIV)-infected individuals are at increased risk for acute and chronic airway disease even though there is no evidence that the virus can infect the lung epithelium
HIV-1 transgene expression caused significant oxidant stress in the lung We first determined the relative levels of glutathione (GSH) and its primary oxidized form, glutathione disulfide (GSSG) in the lung lavage fluids of wild type (WT) and HIV-1 transgenic (HIV-1 Tg) rats
HIV-1 transgene expression was associated with alterations in the tight junction proteins zonula occludens1 and occluding As tight junction proteins mediate the ability of alveolar epithelial cells to regulate paracellular permeability [30], we extended the physiological studies shown in Figure 3 and examined the effects of HIV-1 transgene expression on two key tight junction proteins, namely zonula occludens-1 (ZO-1) and occludin, in the alveolar epithelium
Summary
HIV-infected individuals are at increased risk for acute and chronic airway disease even though there is no evidence that the virus can infect the lung epithelium. The goal of this study was to determine the effects of HIV-1 transgene expression in rats on alveolar epithelial barrier function. Oxidant stress in the alveolar space was determined by measuring the glutathione redox couple by high performance liquid chromatography, and the expression and membrane localization of key tight junction proteins were assessed. The direct effects of the HIV-related proteins gp120 and Tat on alveolar epithelial barrier formation and tight junction protein expression were determined. AIDS Research and Therapy 2009, 6:1 http://www.aidsrestherapy.com/content/6/1/1 infections account for the apparent majority of these lung-related deaths, there is growing evidence that HIV increases the risk of chronic airway diseases such as emphysema. Whether or not chronic HIV infection renders the alveolar epithelium susceptible to injury is unknown
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