High-fat-diet induces airway hyperresponsiveness partly through activating CD38 signaling pathway.

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.