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Environ Health Perspect. 2011 Jun;119(6):784-93. doi: 10.1289/ehp.1002807. Epub 2011 Jan 18.

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

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1
Department of Medicine, Duke University, Durham, North Carolina 27710, USA.

Abstract

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.

PMID:
21245013
PMCID:
PMC3114812
DOI:
10.1289/ehp.1002807
[Indexed for MEDLINE]
Free PMC Article
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