Altered airway responsiveness in CD38-deficient mice
Altered airway responsiveness in CD38-deficient mice
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DOI：
10.1165/rcmb.2004-0243oc
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发表时间：
2005-02-01
影响因子：
6.4
通讯作者：
Kannan, MS
中科院分区：
文献类型：
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作者：
Deshpande, DA;White, TA;Kannan, MS
环adp核糖（cADPR）从细胞内储存中动员钙，并参与激动剂诱导的气道平滑肌（ASM）细胞内钙升高。在这项研究中，我们利用CD38缺陷（CD38(-/-)）小鼠确定了CD38/cADPR信号在气道张力调节中的功能作用。cd38（-/-）小鼠对不同剂量甲胆碱的反应性，通过肺阻力和动态顺应性的变化来确定，与野生型对照相比，cd38（-/-）小鼠对不同剂量甲胆碱的反应性显著（P小于或等于0.05）降低。为了确定反应性降低的机制，我们测量了ASM细胞对收缩激动剂的细胞内钙反应。从cd38（-/-）小鼠分离的ASM细胞中，细胞内钙对乙酰胆碱和内皮素-1的反应明显低于对照组。用cADPR拮抗剂预处理ASM细胞，野生型小鼠分离的细胞对内皮素-1的细胞内钙反应减弱，而cd38（-/-）小鼠分离的细胞内钙反应减弱。在cd38（-/-）小鼠的肺组织中观察到非常低的cADPR水平和未检测到的adp -核糖基环化酶活性，这表明cd38是cADPR合成的关键来源。本研究结果表明，CD38/cADPR通过对激动剂诱导的ASM细胞内钙升高的影响，有助于气道平滑肌张力和反应性。
Cyclic ADP-ribose (cADPR) mobilizes calcium from intracellular stores and contributes to agonist-induced intracellular calcium elevation in airway smooth muscle (ASM). In this study we determined the functional role of CD38/cADPR signaling in the regulation of airway tone using CD38 deficient (cd38(-/-)) mice. The responsiveness to different doses of methacholine, as determined by changes in lung resistance and dynamic compliance, was significantly (P less than or equal to 0.05) lower in cd38(-/-) mice compared with wild-type controls. To determine the mechanism responsible for the reduced responsiveness, we measured the intracellular calcium responses to contractile agonists in ASM cells. In ASM cells isolated from cd38(-/-) mice, the intracellular calcium responses to acetylcholine and endothelin-1 were significantly lower than in controls. Pretreatment of ASM cells with a cADPR antagonist resulted in attenuated intracellular calcium responses to endothelin-1 in cells isolated from wild-type mice, but not in those isolated from the cd38(-/-) mice. Very low cADPR levels and no detectable ADP-ribosyl cyclase activity were observed in lung tissue from cd38(-/-) mice, suggesting that CD38 is a critical source for cADPR synthesis. The results of the present study demonstrate that CD38/cADPR contributes to airway smooth muscle tone and responsiveness through its effects on agonist-induced elevation of intracellular calcium in ASM cells.