HIV-1 transgene expression in rats causes oxidant stress and alveolar epithelial barrier dysfunction.
HIV-1 transgene expression in rats causes oxidant stress and alveolar epithelial barrier dysfunction.
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DOI：
10.1186/1742-6405-6-1
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发表时间：
2009-02-04
影响因子：
2.2
通讯作者：
Guidot, David M
中科院分区：
文献类型：
--
作者：
Lassiter, Coy;Fan, Xian;Joshi, Pratibha C;Jacob, Barbara A;Sutliff, Roy L;Jones, Dean P;Koval, Michael;Guidot, David M
尽管没有证据表明艾滋病毒可以感染肺上皮细胞，但艾滋病毒感染者患急性和慢性气道疾病的风险增加。尽管HIV相关蛋白包括gp 120和达特可直接引起氧化应激和细胞功能障碍，但它们在肺中的作用尚不清楚。本研究的目的是确定HIV-1转基因表达对大鼠肺泡上皮屏障功能的影响。通过测定肺液体清除率和肺泡上皮细胞单层通透性来评估肺泡上皮屏障功能。通过高效液相色谱法测定谷胱甘肽氧化还原对，测定肺泡腔中的氧化应激，并评估关键紧密连接蛋白的表达和膜定位。最后，确定HIV相关蛋白gp 120和达特对肺泡上皮屏障形成和紧密连接蛋白表达的直接影响。HIV-1转基因表达引起肺泡腔内的氧化应激和上皮屏障功能受损，即使没有证据表明气道内有明显的炎症。紧密连接蛋白封闭小带-1和occludin在HIV-1转基因大鼠肺泡上皮细胞中的表达和膜定位减少。此外，在体外用重组gp 120或达特处理野生型大鼠的肺泡上皮单层24小时，再现了对闭锁小带-1和occludin表达和膜定位的许多影响。总之，这些数据表明，HIV相关蛋白引起氧化应激，改变肺泡上皮细胞中关键紧密连接蛋白的表达，导致屏障功能障碍。
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. 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. HIV-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. Taken 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.