Interplay of Soluble, Mechanical and Redox Signaling in Airway Remodeling During Asthma

Abstract

NADPH oxidase 4 (NOX4) is a member of the NADPH oxidase family, encoded by the NOX4 gene, and has been implicated in TGF‐β1‐induced human cardiac fibroblast to myofibroblast differentiation1. NOX4 has been shown to potentiate lung fibroblast differentiation in vitro and its transcript level is enhanced in fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF) compared to normal fibroblasts2. Our lab has previously identified that Transient Receptor Potential Vanilloid 4 (TRPV4), a mechano‐sensitive ion channel, is involved in D. farinae‐induced airway remodeling during asthma in vivo and myofibroblast differentiation in vitro. However, the role of NOX4 in asthma, its interaction with TRPV4, and the mechanism of action still remains elusive. In the present study, we show that NOX4 is up‐regulated during lung remodeling in asthma and fibroblast differentiation in a TRPV4‐dependent pathway. TGF‐β1 treatment up‐regulated NOX4 gene expression and function. Further, employing antioxidants and NOX4 siRNA, our results reveal that NOX4 is involved in TGF‐β1‐induced α smooth muscle actin (αSMA), SM22, fibronectin (FN), myocardin‐related transcription factor‐A (MRTF‐A) and plasminogen activator inhibitor ‐1 (PAI‐1) expression in human lung fibroblasts (hLF). Interestingly, TRPV4 inhibition led to attenuation in TGF‐β1‐mediated NOX4 expression and fibroblast differentiation. Furthermore, NOX4 transcripts were up‐regulated in lung tissues in response to D. farinae in an asthma model supporting our in vitro findings. More importantly, TRPV4−/− mice were protected from D. farinae‐induced asthma and exhibited lower levels of NOX4 gene expression in response to D. farinae, further suggesting that TRPV4 promotes airway remodeling through NOX4.Support or Funding InformationJames Foght research supportThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.