TRPV4-mediated calcium influx into human bronchial epithelia upon exposure to diesel exhaust particles.
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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.
Matrix Metalloproteinase 1
Phospholipase C beta
Pulmonary Disease, Chronic Obstructive
TRPV Cation Channels
Published Version (Please cite this version)10.1289/ehp.1002807
Publication InfoChew, WL; Cho, SH; Ghio, Andrew J; Gilmour, I; Kanju, Patrick; Li, J; ... Yasuda, R (2011). TRPV4-mediated calcium influx into human bronchial epithelia upon exposure to diesel exhaust particles. Environ Health Perspect, 119(6). pp. 784-793. 10.1289/ehp.1002807. Retrieved from http://hdl.handle.net/10161/11673.
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Associate Consulting Professor of Medicine
Professor of Neurology
Research Interests in the Liedtke-Lab: Pain/ nociception Sensory transduction and -transmission TRP ion channels Water and salt equilibrium regulated by the central nervous system Visit the lab's website, download papers and read Dr. Liedtke's CV here.
Adjunct Assistant Professor in the Department of Neurobiology
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