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

Li, Jinju

Kanju, Patrick

Patterson, Michael

Chew, Wei-Leong

Cho, Seung-Hyun

Gilmour, Ian

Oliver, Tim

Yasuda, Ryohei

Ghio, Andrew

Simon, Sidney A

Liedtke, Wolfgang

United States

2016-03-01T15:06:09Z

2011-06

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.

http://www.ncbi.nlm.nih.gov/pubmed/21245013

1552-9924

https://hdl.handle.net/10161/11673

eng

Environmental Health Perspectives

Environ Health Perspect

10.1289/ehp.1002807

Calcium

Cell Line

Humans

Matrix Metalloproteinase 1

Particulate Matter

Phospholipase C beta

Pulmonary Disease, Chronic Obstructive

Receptor, PAR-2

Respiratory Mucosa

Signal Transduction

TRPV Cation Channels

Vehicle Emissions

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

Journal article

Liedtke, Wolfgang|0000-0003-4166-5394

http://www.ncbi.nlm.nih.gov/pubmed/21245013

784

793

6

Anesthesiology

Basic Science Departments

Clinical Science Departments

Duke

Duke Institute for Brain Sciences

Institutes and Provost's Academic Units

Neurobiology

Neurology

Neurology, Headache and Pain

School of Medicine

University Institutes and Centers

Published

119