title: Cigarette Smoke and Estrogen Signaling in Human Airway Smooth Muscle.
abstract: OBJECTIVE
  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 (E2) 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(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.
  
  
  CONCLUSIONS
  These data suggest that CS induces dysregulation of estrogen signaling in ASM, which could contribute to increased airway contractility in women exposed to CS.
authors.affiliation: Departments of Anesthesiology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Venkatachalem
authors.initials: V
authors.lastname: Sathish
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Freeman
authors.forename: Emma
authors.initials: E
authors.lastname: Long
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thompson
authors.forename: Christina M
authors.initials: CM
authors.lastname: Pabelick
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
mesh_terms: D016084:Bronchoconstriction / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D045424:Complex Mixtures / Q000633:toxicity*; D000242:Cyclic AMP / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D012137:Respiratory System / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D000071737:Stromal Interaction Molecule 1; D046509:Tissue Culture Techniques; D014026:Nicotiana / Q000737:chemistry*; D014028:Tobacco Smoke Pollution / Q000032:analysis
chemical_list: D045424:Complex Mixtures; D047628:Estrogen Receptor alpha; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D014028:Tobacco Smoke Pollution; D004958:Estradiol; D006632:Histamine; D000242:Cyclic AMP; D002118:Calcium