TY - JOUR
T1 - Brain-derived neurotrophic factor in cigarette smoke-induced airway hyperreactivity
AU - Sathish, Venkatachalem
AU - VanOosten, Sarah Kay
AU - Miller, Brent S.
AU - Aravamudan, Bharathi
AU - Thompson, Michael A.
AU - Pabelick, Christina M.
AU - Vassallo, Robert
AU - Prakash, Y. S.
PY - 2013/4
Y1 - 2013/4
N2 - Enhanced airway smooth muscle (ASM) contractility contributes to increased resistance to airflow in diseases such as bronchitis and asthmathat occur in passive smokersexposedto secondhandsmoke. 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 ([Ca2+]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 lowaffinity neurotrophin receptors tropomyosin-related kinase (Trk)-B and p75 pan-neurotrophin receptor, respectively. Quantitative ELISA showedthatCSEincreasedBDNFsecretionbyhumanASMcells.BDNF small interfering (si)RNA and/or the chelation of extracellular BDNF, using TrkB-fragment crystallizable, blunted the effects of CSE on [Ca2+]i responses aswell 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.
AB - Enhanced airway smooth muscle (ASM) contractility contributes to increased resistance to airflow in diseases such as bronchitis and asthmathat occur in passive smokersexposedto secondhandsmoke. 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 ([Ca2+]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 lowaffinity neurotrophin receptors tropomyosin-related kinase (Trk)-B and p75 pan-neurotrophin receptor, respectively. Quantitative ELISA showedthatCSEincreasedBDNFsecretionbyhumanASMcells.BDNF small interfering (si)RNA and/or the chelation of extracellular BDNF, using TrkB-fragment crystallizable, blunted the effects of CSE on [Ca2+]i responses aswell 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.
KW - Asthma
KW - Environmental tobacco exposure
KW - Neurotrophin
KW - Secondhand smoke
KW - TrkB
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UR - http://www.scopus.com/inward/citedby.url?scp=84877575355&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2012-0129OC
DO - 10.1165/rcmb.2012-0129OC
M3 - Article
C2 - 23258230
AN - SCOPUS:84877575355
SN - 1044-1549
VL - 48
SP - 431
EP - 438
JO - American journal of respiratory cell and molecular biology
JF - American journal of respiratory cell and molecular biology
IS - 4
ER -