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Transient Receptor Potential Vanilloid 4 (TRPV4) Regulates Fibroblast Differentiation in vitro and D. farinae ‐Induced Airway Remodeling in Asthma in vivo via Modulation of Matrix Synthesis and Matrix Degradation Mechanisms
Author(s) -
Gombedza Farai Colin,
Kondeti Vinay,
AlAzzam Nosayba,
Thodeti Charles,
Paruchuri Sailaja
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.772.2
Subject(s) - trpv4 , fibroblast , extracellular matrix , microbiology and biotechnology , fibronectin , myofibroblast , chemistry , fibrosis , transient receptor potential channel , receptor , biology , pathology , medicine , in vitro , biochemistry
Asthma is a chronic progressive disorder of the airways characterized by inflammation and lung tissue fibrosis. Major features of tissue fibrosis include fibroblast differentiation to contractile myofibroblasts, fibroblast proliferation, and increased synthesis and accumulation of collagen and other extracellular matrix (ECM) proteins. Transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel expressed in lung fibroblasts, responds to changes in ECM stiffness and mechanical forces. Previous studies have shown that, TRPV4 plays a role in the differentiation of cardiac fibroblasts to myofibroblasts. In the present study, we show that TRPV4 mediates lung fibroblast differentiation and aim to elucidate the signaling mechanism(s) involved. We found that TRPV4 was functionally expressed in normal human lung fibroblasts (NHLF) and that knocking‐down of TRPV4 inhibited TGF‐β1 induced fibroblast differentiation, as determined by decreased α‐SMA expression. Similarly, TRPV4 antagonist RN1734 (RN) also significantly inhibited TGF‐β1 induced expression of α‐SMA and fibronectin protein, as well as pro‐fibrotic genes. TRPV4 regulates TGFβ1‐mediated matrix accumulation via two pathways, both dependent on Rho/MRTF‐A. One pathway enhances fibrotic gene expression and matrix deposition via p38 MAPK, while the other pathway activates PAI‐1 and slows down matrix degradation. We also compared TGF‐β1 induced expression levels of these fibrotic markers in NHLF and diseased human lung fibroblasts (DHLF) and found elevated levels in DHLF. To confirm the role of TRPV4 in lung fibroblast differentiation in vivo , we employed a Dermatophagoides farinae ( D. farinae ) induced asthma model in wild‐type (WT) and TRPV4 knock‐out (TRPV4 KO) mice. Following exposure to D. farinae , remodeling and inflammatory responses were enhanced in WT mice while they were completely attenuated in TRPV4 KO mice. Altogether, these findings highlight a major role for TRPV4 in lung fibroblast differentiation and D. farinae induced asthma in mice.