Aerobic Exercise Reduces Airway Smooth Muscle Contraction In Asthmatic Rats Via Inhibition Of Il-4 Secretion And Suppression Of Store-operated Ca2+ Entry

Abstract

PURPOSE: Increasing evidence has shown that aerobic exercise training reduces airway hyperresponsiveness in asthmatic individuals. However, the underlying mechanisms remain elusive. This study aimed to investigate the effect of exercise on airway smooth muscle (ASM) contractile function in asthmatic rats and uncover the possible involvement of interleukin 4 (IL-4) and the store-operated Ca2+ entry (SOCE) pathway. METHODS: Chicken ovalbumin was used to stimulate asthma in male Sprague-Dawley rats. The exercise group received moderate-intensity aerobic exercise training for 4 weeks. IL-4 concentrations in bronchoalveolar lavage fluid (BALF) samples were evaluated by ELISA. The contractile function of the ASM was investigated using tracheal ring tension experiments and intracellular Ca2+ imaging techniques. Western-blot experiments were used to identify expression levels of the calcium-release activated calcium (CRAC) channel protein, Orai, in ASM. RESULTS: The carbachol-stimulated and SOCE-mediated contraction of rat ASM was significantly increased in asthmatic rats, but was abolished by exercise training. Pharmacological studies revealed that GSK5498A, a selective blocker of CRAC channels, significantly inhibited SOCE-induced ASM contraction. In addition, our data showed that aerobic exercise inhibits the up-regulation of IL-4 in BALF as well as Orai protein (subtypes 1 and 2) expression in the ASM of asthmatic rats. In line with these observations, we demonstrated that pretreatment of ASM with IL-4 both up-regulated the expression level of Orai (subtype 1, 2, 3) and promoted carbachol-induced and SOCE-mediated ASM contraction. CONCLUSIONS: The present study revealed that aerobic exercise improved ASM contractile function in asthmatic rats by inhibiting IL-4 secretion and down-regulating the expression levels of Orai, thus decreasing excessive SOCE-mediated ASM contraction in asthmatic rats. Supported by Natural Science Foundation of Guangdong Province (2019A1515012167).