Estrogen modulation of intracellular Ca2+ in airway smooth muscle inflammation

Gender disparity in incidence and severity of asthma is clinically recognized. While estrogen‐induced vasodilation is well‐known, effects on airway smooth muscle (ASM) are controversial. In human ASM, we found that both estrogen receptors (ERs), ERα‐66 and ERβ‐47 are expressed, as are two truncated ERα isoforms (ERα‐36 and ERα‐47). In fura‐2 loaded human ASM cells, acute exposure to 17β‐estradiol (17βE 2 ; 1nM) blunts intracellular calcium ([Ca 2+ ] i ) response to ACh and histamine, effects prevented by ER antagonist. We tested the hypothesis that ERα is the main receptor involved in nongenomic Ca 2+ regulation. Real‐time calcium imaging showed greater decrease in [Ca 2+ ] i with ERα specific agonist R,R THC (10nM) compared to 17βE 2 . TNFα (50ng/ml; 24h) upregulated ERα‐66 but downregulated ERα‐36 expression. TNFα‐induced increase in its receptor TNFRI was blunted by 17βE 2 . Finally, TNFα‐induced enhancement of [Ca 2+ ] i response to histamine was attenuated by ERα activation. These data suggest that in human ASM: 1) nongenomic [Ca 2+ ] i regulation by E 2 involves ERα; b) ERα activation may be beneficial in attenuating inflammatory response to TNFα. Overall, ERs may be a novel therapeutic target in airway diseases such as asthma. Supported by Mayo Graduate School and NIH grant UL1RR024150.