Cigarette Smoke and Estrogen Signaling in Human Airway Smooth Muscle

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.

These data suggest that CS induces dysregulation of estrogen signaling in ASM, which could contribute to increased airway contractility in women exposed to CS.

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.