title: Mechanosensitive transient receptor potential vanilloid 4 regulatesDermatophagoides farinae-induced airway remodelingvia2 distinct pathways modulating matrix synthesis and degradation.
abstract: Contributions of mechanical signals to airway remodeling during asthma are poorly understood. Transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel, has been implicated in cardiac and pulmonary fibrosis; however, its role in asthma remains elusive. Employing aDermatophagoides farinae-induced asthma model, we report here that TRPV4-knockout mice were protected fromD. farinae-induced airway remodeling. Furthermore, lung fibroblasts that were isolated from TRPV4-knockout mice showed diminished differentiation potential compared with wild-type mice. Fibroblasts from asthmatic lung exhibited increased TRPV4 activity and enhanced differentiation potential compared with normal human lung fibroblasts. Of interest, TGF-β1 treatment enhanced TRPV4 activation in a PI3K-dependent manner in normal human lung fibroblastsin vitroMechanistically, TRPV4 modulated matrix remodeling in the lungvia2 distinct but dependent pathways: one enhances matrix deposition by fibrotic gene activation, whereas the other slows down matrix degradation by increased plasminogen activator inhibitor 1. Of importance, both pathways are regulated by Rho/myocardin-related transcription factor-A and contribute to fibroblast differentiation and matrix remodeling in the lung. Thus, our results support a unique role for TRPV4 inD. farinae-induced airway remodeling and warrant further studies in humans for it to be used as a novel therapeutic target in the treatment of asthma.-Gombedza, F., Kondeti, V., Al-Azzam, N., Koppes, S., Duah, E., Patil, P., Hexter, M., Phillips, D., Thodeti, C. K., Paruchuri, S. Mechanosensitive transient receptor potential vanilloid 4 regulatesDermatophagoides farinae-induced airway remodelingvia2 distinct pathways modulating matrix synthesis and degradation.
authors.affiliation: Department of Chemistry, University of Akron, Akron, Ohio, USA; and.
authors.forename: Farai
authors.initials: F
authors.lastname: Gombedza
authors.affiliation: Department of Chemistry, University of Akron, Akron, Ohio, USA; and.
authors.forename: Vinay
authors.initials: V
authors.lastname: Kondeti
authors.affiliation: Department of Chemistry, University of Akron, Akron, Ohio, USA; and.
authors.forename: Nosayba
authors.initials: N
authors.lastname: Al-Azzam
authors.affiliation: Department of Chemistry, University of Akron, Akron, Ohio, USA; and.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Koppes
authors.affiliation: Department of Chemistry, University of Akron, Akron, Ohio, USA; and.
authors.forename: Ernest
authors.initials: E
authors.lastname: Duah
authors.affiliation: Department of Chemistry, University of Akron, Akron, Ohio, USA; and.
authors.forename: Prachi
authors.initials: P
authors.lastname: Patil
authors.affiliation: Department of Chemistry, University of Akron, Akron, Ohio, USA; and.
authors.forename: Madison
authors.initials: M
authors.lastname: Hexter
authors.affiliation: Department of Chemistry, University of Akron, Akron, Ohio, USA; and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Phillips
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA.
authors.forename: Charles K
authors.initials: CK
authors.lastname: Thodeti
authors.affiliation: Department of Chemistry, University of Akron, Akron, Ohio, USA; and sp97@uakron.edu.
authors.forename: Sailaja
authors.initials: S
authors.lastname: Paruchuri
mesh_terms: D000328:Adult; D056151:Airway Remodeling; D000818:Animals; D001249:Asthma / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D040001:Dermatophagoides farinae / Q000276:immunology; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D005353:Fibronectins; D017395:Plasminogen Activator Inhibitor 1; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; D016212:Transforming Growth Factor beta; C486576:Trpv4 protein, mouse; D019869:Phosphatidylinositol 3-Kinases
keywords: PAI-1; PI3K; TGF-β1; fibronectin; myofibroblasts