Smooth muscle brain-derived neurotrophic factor contributes to airway hyperreactivity in a mouse model of allergic asthma

• Published in: The FASEB journal Vol. 33; no. 2; p. 3024
• Main Authors: Britt, Jr, Rodney D, Thompson, Michael A, Wicher, Sarah A, Manlove, Logan J, Roesler, Anne, Fang, Yun-Hua, Roos, Carolyn, Smith, Leslie, Miller, Jordan D, Pabelick, Christina M, Prakash, Y S
• Format: Journal Article
• Language: English
• Published: United States 01.02.2019
• Subjects: Airway Remodeling - drug effects; Allergens - adverse effects; Animals; Asthma - chemically induced; Asthma - physiopathology; Brain-Derived Neurotrophic Factor - physiology; Bronchial Hyperreactivity - etiology; Bronchial Hyperreactivity - metabolism; Bronchial Hyperreactivity - pathology; Disease Models, Animal; Female; Inflammation - etiology; Inflammation - metabolism; Inflammation - pathology; Male; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - physiology; Mice; Mice, Knockout; Mice, Transgenic; Muscle Contraction; Muscle, Smooth - cytology; Muscle, Smooth - metabolism; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - physiology; Pyrazoles - pharmacology; Pyrimidines - pharmacology; Respiratory System - physiopathology; TrkB; fibrosis; neurotrophin; extracellular matrix
• ISSN: 1530-6860
• DOI: 10.1096/fj.201801002R

Recent studies have demonstrated an effect of neurotrophins, particularly brain-derived neurotrophic factor (BDNF), on airway contractility [ via increased airway smooth muscle (ASM) intracellular calcium [Ca ] ] and remodeling (ASM proliferation and extracellular matrix formation) in the context of airway disease. In the present study, we examined the role of BDNF in allergen-induced airway inflammation using 2 transgenic models: 1) tropomyosin-related kinase B (TrkB) conditional knockin (TrkBKI) mice allowing for inducible, reversible disruption of BDNF receptor kinase activity by administration of 1NMPP1, a PP1 derivative, and 2) smooth muscle-specific BDNF knockout (BDNF /SMMHC11 ) mice. Adult mice were intranasally challenged with PBS or mixed allergen ( Alternaria alternata, Aspergillus fumigatus, house dust mite, and ovalbumin) for 4 wk. Our data show that administration of 1NMPP1 in TrkBKI mice during the 4-wk allergen challenge blunted airway hyperresponsiveness (AHR) and reduced fibronectin mRNA expression in ASM layers but did not reduce inflammation per se. Smooth muscle-specific deletion of BDNF reduced AHR and blunted airway fibrosis but did not significantly alter airway inflammation. Together, our novel data indicate that TrkB signaling is a key modulator of AHR and that smooth muscle-derived BDNF mediates these effects during allergic airway inflammation.-Britt, R. D., Jr., Thompson, M. A., Wicher, S. A., Manlove, L. J., Roesler, A., Fang, Y.-H., Roos, C., Smith, L., Miller, J. D., Pabelick, C. M., Prakash, Y. S. Smooth muscle brain-derived neurotrophic factor contributes to airway hyperreactivity in a mouse model of allergic asthma.