Caveolin-1 knockout mice exhibit airway hyperreactivity

被引:32
作者
Aravamudan, Bharathi [1 ]
VanOosten, Sarah K. [1 ]
Meuchel, Lucas W. [2 ,3 ]
Vohra, Pawan [1 ]
Thompson, Michael [1 ]
Sieck, Gary C. [2 ,3 ]
Prakash, Y. S. [1 ,2 ,3 ]
Pabelick, Christina M. [1 ,2 ,3 ]
机构
[1] Mayo Clin, Dept Anesthesiol, Rochester, MN 55905 USA
[2] Mayo Clin, Dept Physiol, Rochester, MN 55905 USA
[3] Mayo Clin, Dept Biomed Engn, Rochester, MN 55905 USA
关键词
bronchial smooth muscle; caveolae; calcium; airway remodeling; epithelium; arginase; NF-KAPPA-B; NITRIC-OXIDE; SMOOTH-MUSCLE; INTRACELLULAR CA2+; CRITICAL REGULATOR; LUNG; ACTIVATION; ARGINASE; PROTEIN; DISRUPTION;
D O I
10.1152/ajplung.00018.2012
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
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.
引用
收藏
页码:L669 / L681
页数:13
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