Guedes Alonso G P, Paulin Jaime, Rivero-Nava Laura, Kita Hirohito, Lund Frances E, Kannan Mathur S
Department of Veterinary Clinicial Sciences, University of Minnesota, St. Paul, MN 55108, USA.
Am J Physiol Lung Cell Mol Physiol. 2006 Dec;291(6):L1286-93. doi: 10.1152/ajplung.00187.2006. Epub 2006 Aug 4.
The transmembrane glycoprotein CD38 in airway smooth muscle is the source of cyclic-ADP ribose, an intracellular calcium-releasing molecule, and is subject to regulatory effects of cytokines such as interleukin (IL)-13, a cytokine implicated in asthma. We investigated the role of CD38 in airway hyperresponsiveness using a mouse model of IL-13-induced airway disease. Wild-type (WT) and CD38-deficient (CD38KO) mice were intranasally challenged with 5 microg of IL-13 three times on alternate days under isoflurane anesthesia. Lung resistance (R(L)) in response to inhaled methacholine was measured 24 h after the last challenge in pentobarbital-anesthetized, tracheostomized, and mechanically ventilated mice. Bronchoalveolar cytokines, bronchoalveolar and parenchymal inflammation, and smooth muscle contractility and relaxation using tracheal segments were also evaluated. Changes in methacholine-induced R(L) were significantly greater in the WT than in the CD38KO mice following intranasal IL-13 challenges. Airway reactivity after IL-13 exposure, as measured by the slope of the methacholine dose-response curve, was significantly higher in the WT than in the CD38KO mice. The rate of isometric force generation in tracheal segments (e.g., smooth muscle reactivity) was greater in the WT than in the CD38KO mice following incubation with IL-13. IL-13 treatment reduced isoproterenol-induced relaxations to similar magnitudes in tracheal segments obtained from WT and CD38KO mice. Both WT and CD38KO mice developed significant bronchoalveolar and parenchymal inflammation after IL-13 challenges compared with naïve controls. The results indicate that CD38 contributes to airway hyperresponsiveness in lungs exposed to IL-13 at least partly by increasing airway smooth muscle reactivity to contractile agonists.
气道平滑肌中的跨膜糖蛋白CD38是环磷酸腺苷核糖（一种细胞内钙释放分子）的来源，并且受到诸如白细胞介素（IL）-13等细胞因子的调节作用，IL-13是一种与哮喘有关的细胞因子。我们使用IL-13诱导的气道疾病小鼠模型研究了CD38在气道高反应性中的作用。在异氟烷麻醉下，野生型（WT）和CD38缺陷型（CD38KO）小鼠每隔一天经鼻给予5微克IL-13，共三次。在最后一次刺激后24小时，对戊巴比妥麻醉、气管切开并机械通气的小鼠测量吸入乙酰甲胆碱后的肺阻力（R(L)）。还评估了支气管肺泡细胞因子、支气管肺泡和实质炎症，以及使用气管段的平滑肌收缩和舒张。鼻内给予IL-13刺激后，WT小鼠中乙酰甲胆碱诱导的R(L)变化显著大于CD38KO小鼠。通过乙酰甲胆碱剂量反应曲线的斜率测量，IL-13暴露后的气道反应性在WT小鼠中显著高于CD38KO小鼠。与IL-13孵育后，WT小鼠气管段的等长力产生速率（例如平滑肌反应性）大于CD38KO小鼠。IL-13处理使WT和CD38KO小鼠气管段中异丙肾上腺素诱导的舒张降低到相似程度。与未处理的对照相比，WT和CD38KO小鼠在IL-13刺激后均出现显著的支气管肺泡和实质炎症。结果表明，CD38至少部分地通过增加气道平滑肌对收缩激动剂的反应性，促成暴露于IL-13的肺部的气道高反应性。
