Institute of Pediatrics, National Key Clinical Specialty of Pediatric Respiratory Medicine, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Discipline of Pediatric Respiratory Medicine, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Int Immunopharmacol. 2018 Mar;56:197-204. doi: 10.1016/j.intimp.2018.01.033. Epub 2018 Feb 2.
CD38 is a plasma membrane bound multifunctional enzyme. It can be activated by inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-13, inducing calcium responses to agonist in airway smooth muscle cells (ASMC). Previous studies have found that high-fat-diet (HFD) induced obesity exhibited innate airway hyperresponsiveness (AHR). This study aimed to detect the effect of CD38 signaling pathway on the AHR of overweight/obese mice. The HFD-fed mice exhibited a significantly higher baseline airway resistance (Rn), and the increasing rates of Rn responded to increasing doses of methacholine compared with the LFD-fed mice. High-fat-diet increased CD38 expressions both in lung tissues and primary cultured ASMCs. Besides, preincubation with TNF-α led to a higher expression of CD38 protein and increased intracellular calcium in ASMC of the HFD-fed mice. Furthermore, CD38 gene knockdown through transfection of CD38 siRNA decreased the concentration of intracellular calcium. Additionally, the upregulations of CD38 protein and CD38 mRNA were also found in the lung tissues of HFD-fed mice challenged by ovalbumin (OVA). Collectively, our findings demonstrated a role of CD38 signaling pathway on the AHR of obesity and might be a potential therapeutic target for treating difficult-to-control obese asthma phenotype.
CD38 是一种位于细胞膜上的多功能酶。它可以被炎症细胞因子（如肿瘤坏死因子-α、白细胞介素-1β）激活，从而诱导气道平滑肌细胞（ASMC）对激动剂产生钙反应。先前的研究发现，高脂肪饮食（HFD）诱导的肥胖表现出固有性气道高反应性（AHR）。本研究旨在检测 CD38 信号通路对超重/肥胖小鼠 AHR 的影响。与低脂饮食喂养的小鼠相比，HFD 喂养的小鼠基础气道阻力（Rn）明显升高，对乙酰甲胆碱剂量增加的 Rn 增加率也升高。高脂肪饮食增加了肺组织和原代培养的 ASMC 中 CD38 的表达。此外，TNF-α 预处理导致 HFD 喂养小鼠的 ASMC 中 CD38 蛋白表达增加和细胞内钙增加。此外，通过转染 CD38 siRNA 敲低 CD38 基因可降低细胞内钙浓度。此外，在 HFD 喂养的小鼠的肺组织中也发现了 CD38 蛋白和 CD38 mRNA 的上调，这些小鼠受到卵清蛋白（OVA）的挑战。综上所述，我们的研究结果表明 CD38 信号通路在肥胖的 AHR 中起作用，可能是治疗难以控制的肥胖型哮喘表型的潜在治疗靶点。
