The long-term administration of Orai 1 antagonist possesses antitussive, bronchodilatory and anti-inflammatory effects in experimental asthma model

摘要

The best-studied store-operated Ca~(2+) channels (SOCs), Ca ~(2+) release activated Ca~(2+) (CRAC) channels, are activated by depleting endoplasmic reticulum Ca~(2+) pool and mediate Ca ~(2+) influx vitally important for Ca~(2+) restoration and many cellular function. CRAC channels were identified on immune and airway smooth muscle (ASM) cells. Emerging evidence points to its involvement in allergic airways diseases. This article evaluated therapeutic potency of CRAC antagonist in experimental animal model of allergic asthma. Allergic asthma, induced by repetitive exposure of guinea pigs to ovalbumine, was followed by 14 days therapy by CRAC antagonist (3-fluoropyridine-4-carboxylic acid, FPCA). In vivo changes of specific airways resistance (sRaw) evaluated bronchodilatory effect of FPCA and salbutamol. The method of citric acid-induced cough reflex assessed antitussive activity of FPCA and codeine. The measurement of exhaled NO (E _(NO)), expression of inducible NO-synthase (iNOS) by RT-PCR and immunohistochemical staining of airways tissue verified anti-inflammatory effect of FPCA. Long-term administration of FPCA resulted in significant cough suppression and bronchodilation, both comparable to the effect of control drugs. FPCA significantly decreased E_(NO) and iNOS expression, which together with immunohistochemical analysis validated its anti-inflammatory effect. Presented data confirmed CRAC channels as a promising target for treatment of respiratory diseases associated with allergic inflammation.