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


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.


CONCLUSIONS
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.
Department of Medicine, Duke University, Durham, North Carolina 27710, USA.
Jinju
J
Li
Patrick
P
Kanju
Michael
M
Patterson
Wei-Leong
WL
Chew
Seung-Hyun
SH
Cho
Ian
I
Gilmour
Tim
T
Oliver
Ryohei
R
Yasuda
Andrew
A
Ghio
Sidney A
SA
Simon
Wolfgang
W
Liedtke
D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D052638:Particulate Matter / Q000633:toxicity*; D054799:Phospholipase C beta / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D044464:Receptor, PAR-2 / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D001335:Vehicle Emissions / Q000633:toxicity
D052638:Particulate Matter; D044464:Receptor, PAR-2; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; D001335:Vehicle Emissions; D054799:Phospholipase C beta; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D002118:Calcium
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