Bronchial asthma is a chronic inflammatory disease characterized by variable airway obstruction and airway hyperresponsiveness (AHR). As is known, interleukin 4 (IL-4) plays an important role in the onset of asthma. Increasing evidence has shown that moderate-intensity aerobic exercise training reduces AHR in patients with asthma. However, the mechanisms underlying exercise-induced improvements in airway smooth muscle (ASM) contractility have not been fully elucidated. Evidence shows that intracellular calcium concentrations ([Ca2+]i) are elevated in ASM of subjects with asthma. Store-operated Ca2+ entry (SOCE) is one of the most important Ca2+ influx pathway of airway smooth muscle cells (ASMC). As a key pore-forming unit of store-operated Ca2+ channels, Orai1 has been demonstrated to play an indispensable role in functional regulation of ASM contraction. We tested the hypothesis that exercise down-regulated the expression of Orai1 in ASM through IL-4-mediated pathways and thus improved asthma symptoms.
Methods:
Male Sprague-Dawley rats (10–12 weeks) were divided into control group, asthma group, and exercise plus asthma group (EA group) randomly. Chicken ovalbumin was used to stimulate asthma, normal saline was applied to the control group. The EA group received a moderate-intensity exercise training 5 times/week for 4 weeks. Bronchoalveolar lavage fluid (BALF) was collected, and IL-4 concentration in BALF was evaluated by ELISA. The rat tracheal tissues were taken and used for ASM cell culture experiments as well as in vitro tracheal ring tension experiments. Western-blot experiment was employed to identify the expression level of Orai1 proteins. [Ca2+]i measurement experiment was used to determine the relative Ca2+ level in ASM cells.
Results:
The contraction of rat airway smooth muscle induced by carbachol was significantly increased with asthma and exercise training reversed this alteration. Meanwhile, the blocker of Orai1 could significantly inhibit carbachol-stimulated ASM constriction. Furthermore, our data showed that asthma increased the carbachol-induced, SOCE-mediated ASM contraction, which was reversed in the EA group. Both of the IL-4 level in BALF and the expression level of Orai1 proteins in ASM of asthmatic rat were upregulated. However, aerobic exercise could down-regulate the IL-4 level and Orai1 protein expression of asthmatic rats. Moreover, we found that application of IL-4 could up-regulate the Orai1 protein expression and the carbachol-induced, SOCE-mediated ASM contraction in ASM cells.
Conclusions:
The present study revealed that aerobic exercise improved the function of asthmatic ASM by inhibiting IL-4 secretion, down-regulating the expression level of Orai1, and thus decreased the excessive ASM contraction of asthmatic rats.

Orail1,exercise,airway smooth muscle,asthma