title: Sex Steroids Influence Brain-Derived Neurotropic Factor Secretion From Human Airway Smooth Muscle Cells.
abstract: Brain derived neurotropic factor (BDNF) is emerging as an important player in airway inflammation, remodeling, and hyperreactivity. Separately, there is increasing evidence that sex hormones contribute to pathophysiology in the lung. BDNF and sex steroid signaling are thought to be intricately linked in the brain. There is currently little information on BDNF and sex steroid interactions in the airway but is relevant to understanding growth factor signaling in the context of asthma in men versus women. In this study, we assessed the effect of sex steroids on BDNF expression and secretion in human airway smooth muscle (ASM). Human ASM was treated with estrogen (E2 ) or testosterone (T, 10 nM each) and intracellular BDNF and secreted BDNF measured. E2 and T significantly reduced secretion of BDNF; effects prevented by estrogen and androgen receptor inhibitor, ICI 182,780 (1 μM), and flutamide (10 μM), respectively. Interestingly, no significant changes were observed in intracellular BDNF mRNA or protein expression. High affinity BDNF receptor, TrkB, was not altered by E2 or T. E2 (but not T) significantly increased intracellular cyclic AMP levels. Notably, Epac1 and Epac2 expression were significantly reduced by E2 and T. Furthermore, SNARE complex protein SNAP25 was decreased. Overall, these novel data suggest that physiologically relevant concentrations of E2 or T inhibit BDNF secretion in human ASM, suggesting a potential interaction of sex steroids with BDNF in the airway that is different from brain. The relevance of sex steroid-BDNF interactions may lie in their overall contribution to airway diseases such as asthma.
authors.affiliation: Department of Respiratory Medicine, First Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi, PR China.|Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Sheng-Yu
authors.initials: SY
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Freeman
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.|Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors.forename: Venkatachalem
authors.initials: V
authors.lastname: Sathish
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thompson
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.|Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Pabelick
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota.|Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
mesh_terms: D056151:Airway Remodeling / Q000235:genetics*; D001249:Asthma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D004967:Estrogens / Q000008:administration & dosage; D005260:Female; D005485:Flutamide / Q000008:administration & dosage; D000077267:Fulvestrant; D005786:Gene Expression Regulation / Q000187:drug effects; D012739:Gonadal Steroid Hormones / Q000008:administration & dosage*; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D020813:Receptor, trkB; D011944:Receptors, Androgen / Q000187:drug effects; D013739:Testosterone / Q000008:administration & dosage
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004967:Estrogens; D012739:Gonadal Steroid Hormones; D008562:Membrane Glycoproteins; D011944:Receptors, Androgen; D000077267:Fulvestrant; D013739:Testosterone; D004958:Estradiol; D005485:Flutamide; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human