title: Estrogen increases nitric-oxide production in human bronchial epithelium.
abstract: Although sex differences in asthma severity are recognized, the mechanisms by which sex steroids such as estrogen influence the airway are still under investigation. Airway tone, a key aspect of asthma, represents a balance between bronchoconstriction and dilation. Nitric oxide (NO) from the bronchial epithelium is an endogenous bronchodilator. We hypothesized that estrogens facilitate bronchodilation by generating NO in bronchial epithelium. In acutely dissociated human bronchial epithelial cells from female patients exposure to 17β-estradiol (E(2); 10 pM-100 nM) resulted in rapid increase of diaminofluorescein fluorescence (NO indicator) within minutes, comparable with that induced by ATP (20 μM). Estrogen receptor (ER) isoform-specific agonists (R,R)-5,11-diethyl-5,6,11,12-tetrahydro-2,8-chrysenediol (THC) (ERα) and diaryl-propionitrile (DPN) (ERβ) stimulated NO production to comparable levels and at comparable rates, whereas the ER antagonist 7α,17β-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol (ICI 182,780) (1 μM) was inhibitory. Estrogen effects on NO were mediated via caveolin-1 (blocked using the caveolin-1 scaffolding domain peptide) and by increased intracellular calcium concentration [prevented by 20 μM 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester but not by blocking Ca(2+) influx using LaCl(3)]. Estrogen increased endothelial NO synthase activation (inhibited by 100 μM N(G)-nitro-l-arginine methyl ester) and phosphorylated Akt. In epithelium-intact human bronchial rings contracted with acetylcholine (1 μM), E(2), THC, and DPN all produced acute bronchodilation in a dose-dependent fashion. Such bronchodilatory effects were substantially reduced by epithelial denudation. Overall, these data indicate that estrogens, acting via ERα or ERβ, can acutely produce NO in airway epithelium (akin to vascular endothelium). Estrogen-induced NO and its impairment may contribute to altered bronchodilation in women with asthma.
authors.affiliation: Department of Physiology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Townsend
authors.forename: Lucas W
authors.initials: LW
authors.lastname: Meuchel
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: D000368:Aged; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D004967:Estrogens / Q000502:physiology*; D005260:Female; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D000077267:Fulvestrant; D006801:Humans; D006834:Hydrazines / Q000378:metabolism; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*; D012737:Sex Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: C105785:1-hexanamine-6-(2-hydroxy-1-methyl-2-nitrosohydrazine)-N-methyl; C112456:4,5-diamino-2-(3,6-dihydroxy-9H-xanthen-9-yl)benzoic acid; D001993:Bronchodilator Agents; D004965:Estrogen Antagonists; D004967:Estrogens; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006834:Hydrazines; D011960:Receptors, Estrogen; D014409:Tumor Necrosis Factor-alpha; D000077267:Fulvestrant; D009569:Nitric Oxide; D004958:Estradiol; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester