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


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.





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Publication Info

Li, Jinju, Andrew J Ghio, Seung-Hyun Cho, Constance E Brinckerhoff, Sidney A Simon and Wolfgang Liedtke (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.

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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 also investigate how these compounds evoke responses in various cortical regions such as the ventral tegmental area, orbitofrontal cortex and gustatory cortex. Our overall goal is to obtain a understanding of the events from the molecular to the behavioral levels that underlie gustatory and irritating sensations produced by chemical stimuli. We collaborate with the Nicolelis and Reinhart laboratories.

Another focus of Dr. Simon's laboratory is to investigate the physical chemical interactions that occur when peptides interact with membranes. To date we have focused on leader sequences. This work is in collaboration with the laboratory of Dr. Tom Mcintosh in the Cell Biology Department.


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.

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