Cellular Physiology and Biochemistry 2015-01-01

Cigarette Smoke and Estrogen Signaling in Human Airway Smooth Muscle.

Venkatachalem Sathish, Michelle R Freeman, Emma Long, Michael A Thompson, Christina M Pabelick, Y S Prakash

Index: Cell Physiol. Biochem. 36 , 1101-15, (2015)

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Abstract

Cigarette smoke (CS) in active smokers and second-hand smoke exposure exacerbate respiratory disorders such as asthma and chronic bronchitis. While women are known to experience a more asthmatic response to CS than emphysema in men, there is limited information on the mechanisms of CS-induced airway dysfunction. We hypothesize that CS interferes with a normal (protective) bronchodilatory role of estrogens, thus worsening airway contractility.We tested effects of cigarette smoke extract (CSE) on 17β-estradiol (E2) signaling in enzymatically-dissociated bronchial airway smooth muscle (ASM) obtained from lung samples of non-smoking female patients undergoing thoracic surgery.In fura-2 loaded ASM cells, CSE increased intracellular calcium ([Ca(2+)]i) responses to 10µM histamine. Acute exposure to physiological concentrations of E2 decreased [Ca(2+)]i responses. However, in 24h exposed CSE cells, although expression of estrogen receptors was increased, the effect of E2 on [Ca(2+)]i was blunted. Acute E2 exposure also decreased store-operated Ca(2+) entry and inhibited stromal interaction molecule 1 (STIM1) phosphorylation: effects blunted by CSE. Acute exposure to E2 increased cAMP, but less so in 24h CSE-exposed cells. 24h CSE exposure increased S-nitrosylation of ERα. Furthermore, 24h CSE-exposed bronchial rings showed increased bronchoconstrictor agonist responses that were not reduced as effectively by E2 compared to non-CSE controls.These data suggest that CS induces dysregulation of estrogen signaling in ASM, which could contribute to increased airway contractility in women exposed to CS.© 2015 S. Karger AG, Basel.