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

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Aims: 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. Methods: We tested effects of cigarette smoke extract (CSE) on 17β-estradiol (E<inf>2</inf>) signaling in enzymatically-dissociated bronchial airway smooth muscle (ASM) obtained from lung samples of non-smoking female patients undergoing thoracic surgery. Results: In fura-2 loaded ASM cells, CSE increased intracellular calcium ([Ca<sup>2+</sup>]<inf>i</inf>) responses to 10µM histamine. Acute exposure to physiological concentrations of E<inf>2</inf> decreased [Ca<sup>2+</sup>]<inf>i</inf> responses. However, in 24h exposed CSE cells, although expression of estrogen receptors was increased, the effect of E<inf>2</inf> on [Ca<sup>2+</sup>]<inf>i</inf> was blunted. Acute E<inf>2</inf> exposure also decreased store-operated Ca<sup>2+</sup> entry and inhibited stromal interaction molecule 1 (STIM1) phosphorylation: effects blunted by CSE. Acute exposure to E<inf>2</inf> 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 E<inf>2</inf> compared to non-CSE controls. Conclusion: These data suggest that CS induces dysregulation of estrogen signaling in ASM, which could contribute to increased airway contractility in women exposed to CS.

Original languageEnglish (US)
Pages (from-to)1101-1115
Number of pages15
JournalCellular Physiology and Biochemistry
DOIs
StateAccepted/In press - Jun 25 2015

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ASJC Scopus subject areas

  • Physiology

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