TRPV4-mediated calcium influx into human bronchial epithelia upon exposure to diesel exhaust particles.

Journal Article (Journal Article)

BACKGROUND: Human respiratory epithelia function in airway mucociliary clearance and barrier function and have recently been implicated in sensory functions. OBJECTIVE: We investigated a link between chronic obstructive pulmonary disease (COPD) pathogenesis and molecular mechanisms underlying Ca2+ influx into human airway epithelia elicited by diesel exhaust particles (DEP). METHODS AND RESULTS: Using primary cultures of human respiratory epithelial (HRE) cells, we determined that these cells possess proteolytic signaling machinery, whereby proteinase-activated receptor-2 (PAR-2) activates Ca2+-permeable TRPV4, which leads to activation of human respiratory disease-enhancing matrix metalloproteinase-1 (MMP-1), a signaling cascade initiated by diesel exhaust particles (DEP), a globally relevant air pollutant. Moreover, we observed ciliary expression of PAR-2, TRPV4, and phospholipase-Cβ3 in human airway epithelia and their DEP-enhanced protein-protein complex formation. We also found that the chronic obstructive pulmonary disease (COPD)-predisposing TRPV4P19S variant enhances Ca2+ influx and MMP 1 activation, providing mechanistic linkage between man-made air pollution and human airway disease. CONCLUSION: DEP evoked protracted Ca2+ influx via TRPV4, enhanced by the COPD-predisposing human genetic polymorphism TRPV4P19S. This mechanism reprograms maladaptive inflammatory and extracellular-matrix-remodeling responses in human airways. The novel concept of air pollution-responsive ciliary signal transduction from PAR-2 to TRPV4 in human respiratory epithelia will accelerate rationally targeted therapies, possibly via the inhalatory route.

Full Text

Duke Authors

Cited Authors

  • Li, J; Kanju, P; Patterson, M; Chew, W-L; Cho, S-H; Gilmour, I; Oliver, T; Yasuda, R; Ghio, A; Simon, SA; Liedtke, W

Published Date

  • June 2011

Published In

Volume / Issue

  • 119 / 6

Start / End Page

  • 784 - 793

PubMed ID

  • 21245013

Pubmed Central ID

  • PMC3114812

Electronic International Standard Serial Number (EISSN)

  • 1552-9924

Digital Object Identifier (DOI)

  • 10.1289/ehp.1002807


  • eng

Conference Location

  • United States