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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 Ca(2+)...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Institute of Environmental Health Sciences
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114812/ https://www.ncbi.nlm.nih.gov/pubmed/21245013 http://dx.doi.org/10.1289/ehp.1002807 |
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author | 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 |
author_facet | 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 |
author_sort | Li, Jinju |
collection | PubMed |
description | 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 Ca(2+) 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 Ca(2+)-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 TRPV4(P19S) variant enhances Ca(2+) influx and MMP 1 activation, providing mechanistic linkage between man-made air pollution and human airway disease. CONCLUSION: DEP evoked protracted Ca(2+) influx via TRPV4, enhanced by the COPD-predisposing human genetic polymorphism TRPV4(P19S). 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. |
format | Online Article Text |
id | pubmed-3114812 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | National Institute of Environmental Health Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-31148122011-06-16 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 Environ Health Perspect Research 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 Ca(2+) 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 Ca(2+)-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 TRPV4(P19S) variant enhances Ca(2+) influx and MMP 1 activation, providing mechanistic linkage between man-made air pollution and human airway disease. CONCLUSION: DEP evoked protracted Ca(2+) influx via TRPV4, enhanced by the COPD-predisposing human genetic polymorphism TRPV4(P19S). 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. National Institute of Environmental Health Sciences 2011-06 2011-01-18 /pmc/articles/PMC3114812/ /pubmed/21245013 http://dx.doi.org/10.1289/ehp.1002807 Text en http://creativecommons.org/publicdomain/mark/1.0/ Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, ?Reproduced with permission from Environmental Health Perspectives?); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright. |
spellingShingle | Research 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 TRPV4-Mediated Calcium Influx into Human Bronchial Epithelia upon Exposure to Diesel Exhaust Particles |
title | TRPV4-Mediated Calcium Influx into Human Bronchial Epithelia upon Exposure to Diesel Exhaust Particles |
title_full | TRPV4-Mediated Calcium Influx into Human Bronchial Epithelia upon Exposure to Diesel Exhaust Particles |
title_fullStr | TRPV4-Mediated Calcium Influx into Human Bronchial Epithelia upon Exposure to Diesel Exhaust Particles |
title_full_unstemmed | TRPV4-Mediated Calcium Influx into Human Bronchial Epithelia upon Exposure to Diesel Exhaust Particles |
title_short | TRPV4-Mediated Calcium Influx into Human Bronchial Epithelia upon Exposure to Diesel Exhaust Particles |
title_sort | trpv4-mediated calcium influx into human bronchial epithelia upon exposure to diesel exhaust particles |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114812/ https://www.ncbi.nlm.nih.gov/pubmed/21245013 http://dx.doi.org/10.1289/ehp.1002807 |
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