Contents lists available at ScienceDirect International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp Preliminary report High-fat-diet induces airway hyperresponsiveness partly through activating CD38 signaling pathway Lei Chong a,1 , Weixi Zhang b,1 , Gang Yu b , Hailin Zhang b , Lili Zhu b , Haiyan Li b , Youyou Shao b , Changchong Li b, ⁎ a Institute of Pediatrics, National Key Clinical Specialty of Pediatric Respiratory Medicine, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China b Discipline of Pediatric Respiratory Medicine, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China ARTICLE INFO Keywords: Airway hyperresponsiveness ASMC Asthma CD38 Overweight/obesity ABSTRACT 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, pre- incubation 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 de- monstrated 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. 1. Introduction Asthma in overweight/obese is a unique asthma phenotype that is quite difficult to manage [1]. It is resistant to available corticosteroid treatments, requires higher medication use, and is associated with fre- quent hospitalizations compared with asthma in normal-weight pa- tients [2–4]. A better understanding of the mechanism underlying the association between overweight/obesity and asthma can guide the de- velopment and delivery of effective treatment for difficult-to-control asthma in the overweight/obese patients. Several studies in the last few years have demonstrated that over- weight/obesity exhibits an innate airway hyperresponsiveness (AHR) [5,6], a hallmark of asthma. Nevertheless, the underlying mechanism is still not clear. AHR is caused by the heightened contraction of airway smooth muscle cells (ASMCs), resulting from increased intracellular calcium responses to spasmogens such as acetylcholine, bradykinin, and endothelin-1 (ET-1) [7–9]. CD38 is a plasma membrane bound multifunctional enzyme induced by cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-13. The upregulation of CD38 can activate its downstream molecule, cyclic adenosine diphosphoribose (cADPR) activity and subsequently intracellular calcium responses to agonists [10]. Recently, some studies have demonstrated a role of CD38 in the regulation of airway smooth muscle (ASM) contraction and AHR induced by allergens [11,12]. The essence of obesity is a systemic inflammation with increased serum concentrations of cytokines, including TNF-α [13]. Therefore, this study proposed the hypothesis that the CD38 signaling pathway might be implicated in overweight/obesity-induced AHR due to the increased concentration of TNF-α, which might aggravate the symp- toms of asthma and increase the incidence of asthma. The present study was conducted to examine the effect of CD38 signaling pathway on the AHR of overweight/obesity mice. https://doi.org/10.1016/j.intimp.2018.01.033 Received 28 November 2017; Received in revised form 19 January 2018; Accepted 22 January 2018 ⁎ Corresponding author. 1 Lei Chong and Weixi Zhang devote equally to this article. E-mail address: wzlichch@163.com (C. Li). Abbreviations: AHR, airway hyperresponsiveness; Rn, airway resistance; BMI, body mass index; cADPR, cyclic adenosine diphosphoribose; BALF, bronchoalveolar lavage fluid; ASMC, airway smooth muscle cell; HFD, high-fat-diet; OVA, ovalbumin International Immunopharmacology 56 (2018) 197–204 1567-5769/ © 2018 Elsevier B.V. All rights reserved. T