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Diesel exhaust particles activate the matrix-metalloproteinase-1 gene in human bronchial epithelia in a beta-arrestin-dependent manner via activation of RAS.

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Date
2009-03
Authors
Li, Jinju
Ghio, Andrew J
Cho, Seung-Hyun
Brinckerhoff, Constance E
Simon, Sidney A
Liedtke, Wolfgang
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Abstract
BACKGROUND: Diesel exhaust particles (DEPs) are globally relevant air pollutants that exert a detrimental human health impact. However, mechanisms of damage by DEP exposure to human respiratory health and human susceptibility factors are only partially known. Matrix metalloproteinase-1 (MMP-1) has been implied as an (etio)pathogenic factor in human lung and airway diseases such as emphysema, chronic obstructive pulmonary disease, chronic asthma, tuberculosis, and bronchial carcinoma and has been reported to be regulated by DEPs. OBJECTIVE: We elucidated the molecular mechanisms of DEPs' up-regulation of MMP-1. METHODS/RESULTS: Using permanent and primary human bronchial epithelial (HBE) cells at air-liquid interface, we show that DEPs activate the human MMP-1 gene via RAS and subsequent activation of RAF-MEK-ERK1/2 mitogen-activated protein kinase signaling, which can be scaffolded by beta-arrestins. Short interfering RNA mediated beta-arrestin1/2 knockout eliminated formation, subsequent nuclear trafficking of phosphorylated ERK1/2, and resulting MMP-1 transcriptional activation. Transcriptional regulation of the human MMP-1 promoter was strongly influenced by the presence of the -1607GG polymorphism, present in 60-80% of humans, which led to striking up-regulation of MMP-1 transcriptional activation. CONCLUSION: Our results confirm up-regulation of MMP-1 in response to DEPs in HBE and provide new mechanistic insight into how these epithelia, the first line of protection against environmental insults, up-regulate MMP-1 in response to DEP inhalation. These mechanisms include a role for the human -1607GG polymorphism as a susceptibility factor for an accentuated response, which critically depends on the ability of beta-arrestin1/2 to generate scaffolding and nuclear trafficking of phosphorylated ERK1/2.
Type
Journal article
Subject
MAP kinase
MMP-1
MMP-1 promoter polymorphism
bronchial epithelia
diesel particles
urban smog
β-arrestin
Analysis of Variance
Arrestins
Blotting, Western
Bronchi
Cell Line
DNA Primers
Enzyme-Linked Immunosorbent Assay
Gene Expression Regulation, Enzymologic
Humans
Immunohistochemistry
Matrix Metalloproteinase 1
Respiratory Mucosa
Reverse Transcriptase Polymerase Chain Reaction
Vehicle Emissions
beta-Arrestins
ras Proteins
Permalink
https://hdl.handle.net/10161/11672
Published Version (Please cite this version)
10.1289/ehp.0800311
Publication Info
Li, Jinju; Ghio, Andrew J; Cho, Seung-Hyun; Brinckerhoff, Constance E; Simon, Sidney A; & Liedtke, Wolfgang (2009). Diesel exhaust particles activate the matrix-metalloproteinase-1 gene in human bronchial epithelia in a beta-arrestin-dependent manner via activation of RAS. Environ Health Perspect, 117(3). pp. 400-409. 10.1289/ehp.0800311. Retrieved from https://hdl.handle.net/10161/11672.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Liedtke

Wolfgang Bernhard Liedtke

Adjunct Professor in the Department 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.

Sidney Arthur Simon

Professor Emeritus of Neurobiology
Dr. Simon's laboratory studies the interaction of chemical stimuli with cultured and intact trigeminal ganglion neurons and taste receptor cells both in culture, in anesthetized and in awake behaving animals. We investigate how chemicals that are either bitter and/or irritating ( e.g., nicotine, capsaicin, colloidal particles) interact with particular types of receptors (e.g. nicotinic acetylcholine receptors or vanilloid receptors) to produce a bitter, irritating or painful sensation. We a
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