Abstract
Prior studies revealed increased expression of the transient receptor potential vanilloid-3 (TRPV3) ion channel following wood smoke particulate matter (WSPM) treatment of human bronchial epithelial cells (HBECs). TRPV3 attenuated pathological endoplasmic reticulum stress and cytotoxicity mediated by TRP ankyrin-1 (TRPA1). Here, the basis for how TRPV3 expression is regulated by cell injury, the effects this has on HBEC physiology and WSPM-induced airway remodeling in mice was investigated. TRPV3 mRNA was rapidly increased in HBECs treated with WSPM and after monolayer damage caused by tryptic disruption, scratch wounding, and cell passaging. TRPV3 mRNA abundance varied with time, and stimulated expression occurred independent of new protein synthesis. Over-expression of TRPV3 in HBECs reduced cell migration and wound repair, while enhancing cell adhesion. This phenotype correlated with disrupted mRNA expression of ligands of the epidermal growth factor, tumor growth factor-b, and frizzled receptors. Accordingly, delayed wound repair by TRPV3 overexpressing cells was reversed by growth factor supplementation. In normal HBECs, TRPV3 up-regulation was triggered by exogenous growth factor supplementation, and was attenuated by inhibitors of growth factor receptor signaling. In mice, sub-acute oropharyngeal instillation with WSPM also promoted TRPV3 mRNA expression and epithelial remodeling, which was attenuated by TRPV3 antagonist pre- and co-treatment. This latter effect may be the consequence of antagonist-induced TRPV3 expression. These findings provide insights into the roles of TRPV3 in lung epithelial cells under basal and dynamic states, as well as highlight potential roles for TRPV3 ligands in modulating epithelial damage/repair.
Significance Statement Coordinated epithelial repair is essential for the maintenance of the airways, with deficiencies and over- repair associated with adverse consequences to respiratory health. This study shows that TRPV3, an ion channel, is involved in coordinating repair through integrated repair signaling pathways, wherein TRPV3 expression is up-regulated immediately following injury, and return to basal levels as cells complete the repair process. TRPV3 may be a novel target for understanding and/or treating conditions in which airway/lung epithelial repair is not properly orchestrated.
- epidermal growth factor (EGF) receptors
- epithelial cells
- growth factors
- pulmonary pharmacology
- pulmonary toxicology
- transforming growth factor (TGF)
- transient receptor potential (TRP) receptors
- Wnt / b-catenin
- Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics