title: Brain-derived neurotrophic factor in cigarette smoke-induced airway hyperreactivity.
abstract: Enhanced airway smooth muscle (ASM) contractility contributes to increased resistance to airflow in diseases such as bronchitis and asthma that occur in passive smokers exposed to secondhand smoke. Little information exists on the cellular mechanisms underlying such airway hyperreactivity. Sputum samples of patients with chronic sinusitis, bronchitis, and asthma show increased concentrations of growth factors called neurotrophins, including brain-derived growth factor (BDNF), but their physiological significance remains unknown. In human ASM, we tested the hypothesis that BDNF contributes to increased contractility with cigarette smoke exposure. The exposure of ASM to 1% or 2% cigarette smoke extract (CSE) for 24 hours increased intracellular calcium ([Ca(2+)](i)) responses to histamine, and further potentiated the enhancing effects of a range of BDNF concentrations on such histamine responses. CSE exposure increased the expression of the both high-affinity and low-affinity neurotrophin receptors tropomyosin-related kinase (Trk)-B and p75 pan-neurotrophin receptor, respectively. Quantitative ELISA showed that CSE increased BDNF secretion by human ASM cells. BDNF small interfering (si)RNA and/or the chelation of extracellular BDNF, using TrkB-fragment crystallizable, blunted the effects of CSE on [Ca(2+)](i) responses as well as the CSE enhancement of cell proliferation, whereas TrkB siRNA blunted the effects of CSE on ASM contractility. These data suggest that cigarette smoke is a potent inducer of BDNF and TrkB expression and signaling in ASM, which then contribute to cigarette smoke-induced airway hyperresponsiveness.
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Venkatachalem
authors.initials: V
authors.lastname: Sathish
authors.forename: Sarah Kay
authors.initials: SK
authors.lastname: Vanoosten
authors.forename: Brent S
authors.initials: BS
authors.lastname: Miller
authors.forename: Bharathi
authors.initials: B
authors.lastname: Aravamudan
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thompson
authors.forename: Christina M
authors.initials: CM
authors.lastname: Pabelick
authors.forename: Robert
authors.initials: R
authors.lastname: Vassallo
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
mesh_terms: D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006632:Histamine / Q000378:metabolism; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D020813:Receptor, trkB / Q000096:biosynthesis; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism / Q000473:pathology; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; D014028:Tobacco Smoke Pollution; D006632:Histamine; D020813:Receptor, trkB; D002118:Calcium