Mechanisms of BDNF regulation in asthmatic airway smooth muscle.
Brain-derived neurotrophic factor (BDNF), a neurotrophin produced by airway smooth muscle (ASM), enhances inflammation effects on airway contractility, supporting the idea that locally produced growth factors influence airway diseases such as asthma. We endeavored to dissect intrinsic mechanisms regulating endogenous, as well as inflammation (TNF-α)-induced BDNF secretion in ASM of nonasthmatic vs. asthmatic humans. We focused on specific Ca(2+) regulation- and inflammation-related signaling cascades and quantified BDNF secretion. We find that TNF-α enhances BDNF release by ASM cells, via several mechanisms relevant to asthma, including transient receptor potential channels TRPC3 and TRPC6 (but not TRPC1), ERK 1/2, PI3K, PLC, and PKC cascades, Rho kinase, and transcription factors cAMP response element binding protein and nuclear factor of activated T cells. Basal BDNF expression and secretion are elevated in asthmatic ASM and increase further with TNF-α exposure, involving many of these regulatory mechanisms. We conclude that airway BDNF secretion is regulated at multiple levels, providing a basis for autocrine effects of BDNF under conditions of inflammation and disease, with potential downstream influences on contractility and remodeling.
Departments of Anesthesiology, Mayo Clinic, Rochester, Minnesota; and.
Bharathi
B
Aravamudan
Departments of Anesthesiology, Mayo Clinic, Rochester, Minnesota; and.
Michael A
MA
Thompson
Departments of Anesthesiology, Mayo Clinic, Rochester, Minnesota; and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
Christina M
CM
Pabelick
Departments of Anesthesiology, Mayo Clinic, Rochester, Minnesota; and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota prakash.ys@mayo.edu.
Y S
YS
Prakash
D056151:Airway Remodeling; D001249:Asthma / Q000378:metabolism* / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D001980:Bronchi / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D011401:Promoter Regions, Genetic; D055571:Secretory Pathway; D015398:Signal Transduction; D050052:TRPC Cation Channels / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D050052:TRPC Cation Channels; C579455:BDNF protein, human
airway; asthma; brain-derived neurotrophic factor; inflammation; neurotrophin; secretion