CD38 and airway hyper-responsiveness: studies on human airway smooth muscle cells and mouse models.
CD38 and airway hyper-responsiveness: studies on human airway smooth muscle cells and mouse models.
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DOI：
10.1139/cjpp-2014-0410
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发表时间：
2015-02
影响因子：
2.1
通讯作者：
Kannan MS
中科院分区：
文献类型：
--
作者：
Guedes AG;Deshpande DA;Dileepan M;Walseth TF;Panettieri RA Jr;Subramanian S;Kannan MS
哮喘是一种炎症性疾病，其中改变的钙调节、收缩性和气道平滑肌（ASM）增殖促成气道高反应性和气道壁重塑。CD 38（一种在人ASM细胞中表达的细胞表面蛋白）的酶活性产生钙动员第二信使分子，如环状ADP-核糖。人ASM细胞中的CD 38表达通过细胞因子（例如TNF-α）增强，所述细胞因子需要MAP激酶和转录因子NF-κ B和AP-1的活化，并且通过与CD 38的3'非翻译区结合以及通过调节参与其调节的信号传导机制的活化而由miR-140- 3 p和miR-708进行转录后调节。与野生型小鼠相比，CD 38缺陷小鼠对吸入乙酰甲胆碱的气道反应性降低。与野生型小鼠相比，用TNF-α或IL-13或环境真菌互隔交链孢菌鼻内激发CD 38缺陷小鼠可导致乙酰甲胆碱反应性显著减弱，气道炎症相当。相互骨髓移植研究表明，部分恢复气道高反应性吸入乙酰甲胆碱在镉38缺陷小鼠。这些研究为CD 38参与气道高反应性的发展提供了证据，气道高反应性是哮喘的标志性特征。未来的研究旨在药物发现和递送靶向CD 38表达和/或活性是必要的。
Asthma is an inflammatory disease in which altered calcium regulation, contractility and airway smooth muscle (ASM) proliferation contribute to airway hyperresponsiveness and airway wall remodeling. The enzymatic activity of CD38, a cell-surface protein expressed in human ASM cells, generates calcium mobilizing second messenger molecules such as cyclic ADP-ribose. CD38 expression in human ASM cells is augmented by cytokines (e.g. TNF-α) that requires activation of MAP kinases and the transcription factors, NF-ƙB and AP-1 and post-transcriptionally regulated by miR-140-3p and miR-708 by binding to 3’ Untranslated Region of CD38 as well as by modulating the activation of signaling mechanisms involved in its regulation. Mice deficient in CD38 exhibit reduced airway responsiveness to inhaled methacholine relative to response in wild-type mice. Intranasal challenge of CD38 deficient mice with TNF-α or IL-13, or the environmental fungus Alternaria alternata, causes significantly attenuated methacholine responsiveness compared to wild-type mice, with comparable airway inflammation. Reciprocal bone marrow transfer studies revealed partial restoration of airway hyperresponsiveness to inhaled methacholine in the Cd38 deficient mice. These studies provide evidence for CD38 involvement in the development of airway hyperresponsiveness, a hallmark feature of asthma. Future studies aimed at drug discovery and delivery targeting CD38 expression and/or activity are warranted.