TRPV3 drives lung injury by sensing inflammatory signals to disrupt alveolar epithelial barrier and promote inflammation.

Abstract

Background and purpose: Pulmonary inflammation is a central pathological feature of many respiratory diseases. Transient receptor potential vanilloid 3 (TRPV3), a non-selective cation channel abundantly expressed in the skin, nerve and lung tissues, is involved in itch, skin inflammation and barrier regulation. However, its function in the pulmonary system remains elusive. We aimed to determine whether and how TRPV3 is involved in pulmonary inflammation.

Experimental approach: Lipopolysaccharide (LPS) and carvacrol were used to model acute lung injury (ALI) in C57BL/6J mice. Histology, bronchoalveolar lavage fluid analysis, qPCR, Western blotting, immunofluorescence, Ca²⁺ imaging, transepithelial electrical resistance and FITC-dextran permeability assays were used to assess inflammatory cell infiltration, cytokine expression, intracellular Ca²⁺ changes and epithelial barrier integrity.

Key results: TRPV3 expression is markedly up-regulated in lung tissues of ALI mice. Pharmacological activation of TRPV3 by carvacrol triggers features of ALI. Genetic deletion or pharmacological inhibition of TRPV3 significantly attenuated LPS- or carvacrol-induced lung injury. Activating TRPV3 in cultured alveolar epithelial cells increased intracellular Ca²⁺, boosted cytokine/chemokine production, disrupted tight junctions, reduced transepithelial electrical resistance and increased epithelial permeability. TNF-α augmented TRPV3 Ca²⁺ responses, and inhibition of TRPV3 activity or suppression of TRPV3 expression abolished TNF-α-induced production of cytokines/chemokines and tight junction disruption.

Conclusions and implications: TRPV3 senses inflammatory signals to augment inflammation and disrupt tight junctions in alveolar epithelial cells, making it a promising molecular target to develop treatments for pulmonary inflammation.