β2-adrenergic receptor overexpression increases alveolar fluid clearance and responsiveness to endogenous catecholamines in rats
β2-adrenergic receptor overexpression increases alveolar fluid clearance and responsiveness to endogenous catecholamines in rats
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DOI：
10.1161/hh2201.100204
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发表时间：
2001-11-09
影响因子：
20.1
通讯作者：
Factor, P
中科院分区：
文献类型：
--
作者：
Dumasius, V;Sznajder, JI;Factor, P
β-肾上腺素能激动剂通过增加上皮溶质转运蛋白如阿米洛利敏感性上皮Na+通道（ENaC）和Na，K-ATP酶的表达和活性来加速肺泡液的清除。我们在此报道腺病毒介导的人β 2肾上腺素能受体（β 2 AR）cDNA的过表达增加了人肺上皮细胞（A549）中β 2 AR mRNA、膜结合受体蛋白表达和受体功能（丙卡特罗诱导的cAMP产生）。受体过表达与基底外侧细胞膜中儿茶酚胺（丙卡特罗）响应性主动Na+转运增加和Na，K-ATP酶丰度增加相关。将β（2）AR基因转移到正常大鼠的肺泡上皮细胞，可改善膜结合β（2）AR的表达和功能，并分别增加从外周肺分离的顶侧和基底侧细胞膜组分中的ENaC（α亚基）丰度和Na，K-ATP酶活性。在β 2 AR过度表达的大鼠中，肺泡液体清除率（AFC）（主动Na+转运的指标）比假感染对照组和用不表达cDNA的腺病毒感染的大鼠高100%。在β 2 AR过度表达的肺中加入β 2 AR特异性激动剂丙卡特罗并没有进一步增加AFC。在肾上腺切除或心得安治疗的大鼠中，β（2）AR过表达肺的AFC显示清除率与正常、未治疗、假感染对照组相同或更低。这些实验表明，肺泡β 2 AR过表达可改善β 2 AR功能，并通过改善对内源性儿茶酚胺的反应性，最大程度地上调β激动剂反应性主动Na+转运。这些研究表明，上调β 2 AR功能可能有一天被证明对治疗肺水肿有用。
beta -Adrenergic agonists accelerate the clearance of alveolar fluid by increasing the expression and activity of epithelial solute transport proteins such as amiloride-sensitive epithelial Na+ channels (ENaC) and Na,K-ATPases. Here we report that adenoviral-mediated overexpression of a human beta (2)-adrenergic receptor (beta (2)AR) cDNA increases beta (2)AR mRNA, membrane-bound receptor protein expression, and receptor function (procaterol-induced cAMP production) in human lung epithelial cells (A549). Receptor overexpression was associated with increased catecholamine (procaterol)responsive active Na+ transport and increased abundance of Na,K-ATPases in the basolateral cell membrane. beta (2)AR gene transfer to the alveolar epithelium of normal rats improved membrane-bound beta (2)AR expression and function and increased levels of ENaC (alpha subunit) abundance and Na,K-ATPases activity in apical and basolateral cell membrane fractions isolated from the peripheral lung, respectively. Alveolar fluid clearance (AFC), an index of active Na+ transport, in beta (2)AR overexpressing rats was up to 100% greater than sham-infected controls and rats infected with an adenovirus that expresses no cDNA. The addition of the beta (2)AR-specific agonist procaterol to beta (2)AR overexpressing lungs did not increase AFC further. AFC in beta (2)AR overexpressing lungs from adrenalectomized or propranolol-treated rats revealed clearance rates that were the same or less than normal, untreated, sham-infected controls. These experiments indicate that alveolar beta (2)AR overexpression improves beta (2)AR function and maximally upregulates beta -agonist-responsive active Na+ transport by improving responsiveness to endogenous catecholamines. These studies suggest that upregulation o beta (2)AR function may someday prove useful for the treatment of pulmonary edema.