A2B adenosine receptors regulate the mucus clearance component of the lung's innate defense system
A2B adenosine receptors regulate the mucus clearance component of the lung's innate defense system
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DOI：
10.1165/rcmb.2007-0450oc
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发表时间：
2008-08-01
影响因子：
6.4
通讯作者：
Tarran, Robert
中科院分区：
文献类型：
--
作者：
Rollins, Brett M.;Burn, Mellisa;Tarran, Robert
腺苷（ADO）信号在哮喘和慢性阻塞性肺疾病中均发生改变，A（2B）腺苷受体（A（2B）-R）可能驱动肺部炎症。因此，已经提出特异性抑制A（2B）-R可以治疗炎性肺病。然而，ADO对囊性纤维化跨膜传导调节因子（CFTR）的刺激可能在允许浅表上皮维持气道表面液体（ASL）体积方面至关重要，这是确保粘液水合和可清除所需的。我们的目标是确定ADO受体（ADO-R）的基础ASL容量调节支气管上皮细胞。我们使用PCR技术来确定ADO-R在支气管上皮细胞中的表达，并使用鼻电位差测量、Ussing室研究和XZ共聚焦显微镜来观察Cl-分泌和ASL体积调节。A（2B）-R是人支气管上皮细胞供体标本中表达最高的ADO-R，体内ADO-R的抑制可防止CFTR的激活。A2 B-R是在培养的人支气管上皮细胞中检测到的唯一ADO-R，并且用特异性A2 B-R拮抗剂抑制该受体导致ASL高度塌陷和未能影响ASL高度稳态。用ADO脱氨酶去除ADO并用5 'N-乙基羧酰胺腺苷替代，导致ASL高度的剂量依赖性变化，并表明细胞表面（ADO）可能超过1 μ M，这足以激活A2 B-R。A2 B-R是人体气道ASL体积稳态所必需的，针对抑制A2 B-R的治疗可能导致ASL体积耗尽和粘液淤积的囊性纤维化样表型。
Adenosine (ADO) signaling is altered in both asthma and chronic obstructive pulmonary disease, and the A(2B) adenosine receptor (A(2B)-R) may drive pulmonary inflammation. Accordingly, it has been proposed that specific inhibition of the A(2B)-R could treat inflammatory lung diseases. However, stimulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by ADO may be crucial in permitting the superficial epithelium to maintain airway surface liquid (ASL) volume, which is required to ensure hydrated and clearable mucus. Our goal was to determine which ADO receptor (ADO-R) underlies ASL volume regulation in bronchial epithelia. We used PCR techniques to determine ADO-R expression in bronchial epithelia and used nasal potential difference measurements, Ussing chambers studies, and XZ-confocal microscopy to look at Cl- secretion and ASL volume regulation. The A(2B)-R was the most highly expressed ADO-R in donor specimens of human bronchial epithelia, and inhibition of ADO-R in vivo prevented activation of CFTR. A2B-R was the only ADO-R detected in cultured human bronchial epithelial cells and inhibition of this receptor with specific A2B-R antagonists resulted in ASL height collapse and a failure to effect ASL height homeostasis. Removal of ADO with ADO deaminase and replacement with 5'N-ethylcarboxamide adenosine resulted in dose-dependent changes in ASL height, and suggested that the cell surface (ADO) may be in excess of I mu M, which is sufficient to activate A2B-R. A2B-R are required for ASL volume homeostasis in human airways, and therapies directed at inhibiting A2B-R may lead to a cystic fibrosis-like phenotype with depleted ASL volume and mucus stasis.