Caveolin-1 knockout mice exhibit airway hyperreactivity
Caveolin-1 knockout mice exhibit airway hyperreactivity
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DOI：
10.1152/ajplung.00018.2012
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发表时间：
2012-10-01
影响因子：
4.9
通讯作者：
Pabelick, Christina M.
中科院分区：
文献类型：
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作者：
Aravamudan, Bharathi;VanOosten, Sarah K.;Pabelick, Christina M.
Aravamudan B, VanOosten SK, Meuchel LW, Vohra P, Thompson M, Sieck GC, Prakash YS, Pabelick CM。Caveolin-1敲除小鼠表现出气道高反应性。[J] .中国生物医学工程学报，2016,31(4):559 - 561。首次发表于2012年8月24日；doi: 10.1152 / ajplung.00018.2012。小泡是表达支架小泡蛋白的瓶状质膜内陷。虽然在内皮和上皮中发现了小窝蛋白（它们调节一氧化氮合酶活性），但它们在平滑肌中的作用仍在研究中。我们和其他人之前已经表明，人气道平滑肌（ASM）的小窝，表达小窝蛋白-1，含有Ca2+和力调节蛋白，并参与介导炎症细胞因子如tnf - α对细胞内Ca2+浓度对激动剂的反应的影响。因此，我们使用敲除（KO） （Cav1 KO）小鼠和卵清蛋白致敏/激发（OVA）过敏性气道高反应性模型，在体内验证了caveolin-1缺失导致气道高反应性降低的假设。令人惊讶的是，使用FlexiVent系统测试的气道对甲胆碱的反应性在Cav1 KO对照（CTL）和KO OVA小鼠中增加，这不能用对OVA的钝化免疫反应来解释。在野生型（WT） OVA小鼠的ASM中，小泡蛋白1、小泡转换蛋白cavins 1-3、小泡相关Ca2+和力调节蛋白Orai1、RhoA的表达均升高，而在Cav1 KO CTL和OVA小鼠中不存在这种作用。然而，与WT OVA一样，CTL和OVA Cav1 KO气道均表现出增强的重塑迹象，增殖标志物高表达，胶原蛋白增加。另外，三组气道上皮细胞内皮型一氧化氮合酶和精氨酸酶表达均较低，但诱导型一氧化氮合酶和精氨酸酶表达较高。精氨酸酶活性也在这三组中增加，抑制剂no - noha （n -omega-no - l -精氨酸）增强了离体气管环对乙酰胆碱的敏感性，尤其是在Cav1 KO小鼠中。基于这些数据反驳了我们最初的假设，我们得出结论，caveolin-1对ASM和上皮具有复杂的影响，导致气道重构和支气管扩张改变介导的气道高反应性。
Aravamudan B, VanOosten SK, Meuchel LW, Vohra P, Thompson M, Sieck GC, Prakash YS, Pabelick CM. Caveolin-1 knockout mice exhibit airway hyperreactivity. Am J Physiol Lung Cell Mol Physiol 303: L669-L681, 2012. First published August 24, 2012; doi:10.1152/ajplung.00018.2012.-Caveolae are flask-shaped plasma membrane invaginations expressing the scaffolding caveolin proteins. Although caveolins have been found in endothelium and epithelium (where they regulate nitric oxide synthase activity), their role in smooth muscle is still under investigation. We and others have previously shown that caveolae of human airway smooth muscle (ASM), which express caveolin-1, contain Ca2+ and force regulatory proteins and are involved in mediating the effects of inflammatory cytokines such as TNF-alpha on intracellular Ca2+ concentration responses to agonist. Accordingly, we tested the hypothesis that in vivo, absence of caveolin-1 leads to reduced airway hyperresponsiveness, using a knockout (KO) (Cav1 KO) mouse and an ovalbumin-sensitized/challenged (OVA) model of allergic airway hyperresponsiveness. Surprisingly, airway responsiveness to methacholine, tested by use of a FlexiVent system, was increased in Cav1 KO control (CTL) as well as KO OVA mice, which could not be explained by a blunted immune response to OVA. In ASM of wild-type (WT) OVA mice, expression of caveolin-1, the caveolar adapter proteins cavins 1-3, and caveolae-associated Ca2+ and force regulatory proteins such as Orai1 and RhoA were all increased, effects absent in Cav1 KO CTL and OVA mice. However, as with WT OVA, both CTL and OVA Cav1 KO airways showed signs of enhanced remodeling, with high expression of proliferation markers and increased collagen. Separately, epithelial cells from airways of all three groups displayed lower endothelial but higher inducible nitric oxide synthase and arginase expression. Arginase activity was also increased in these three groups, and the inhibitor nor-NOHA (N-omega-nor-L-arginine) enhanced sensitivity of isolated tracheal rings to ACh, especially in Cav1 KO mice. On the basis of these data disproving our original hypothesis, we conclude that caveolin-1 has complex effects on ASM vs. epithelium, resulting in airway hyperreactivity in vivo mediated by altered airway remodeling and bronchodilation.