Induction of airway smooth muscle proliferation and airway hyperreactivity after exposure to airborne particles
| Project/Area Number |
18590866
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | Tokyo Women's Medical University |
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Principal Investigator |
TAMAOKI Jun Tokyo Women's Medical University, Medicine, Professor (60147395)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,920,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | Airway smooth muscle / Remodeling / Cell proliferation / Epidermal growth factor / Asthma / Air pollution / Ultrafine particle / Protein synthesis / 蛋白合成 |
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| Research Abstract |
In this in vitro and in vivo experiments, exposure to ambient ultrafine particles induced airway inflammatory reactions and tissue remodelling, as well as airway hyperresponsiveness. To determine whether ultrafine carbon black (ufCB) affects proliferation of airway smooth muscle cells and, if so, what the mechanism of action is, we studied human primary bronchial smooth muscle cell cultures. Incubation of cells in the serum-free medium with ufCB increased incorporations of [3H]-thymidine and [3H]-leucine into cells in a time- and dose dependent manner. This effect was attenuated by a free radical scavenger and a NADH/NADPH oxidase inhibitor, and completely inhibited by pretreatment with the epidermal growth factor receptor (EGF-R) tyrosine kinase inhibitors AG1478 and BIBX1382, and the mitogen-activated protein kinase (MEK) inhibitor PD98059. Transfection of a dominant negative mutant of H-Ras likewise abolished the effect ufCB. Stimulation with ufCB also induced processing of membrane anchored pro-heparin-binding (HB) -EGF, release of soluble HB-EGF into the medium, association of phosphorylated EGF-R and Shc with glutathione-S-transferase-Grb2 fusion protein, and phosphorylation of extracellular signal-regulated kinase (ERK) . Pretreatment with each AG1478, [Glu^52]Diphtheria toxin, a specific inhibitor of HB-EGF, and neutralizing HB-EGF antibody inhibited ufCB-induced ERK activation. Furthermore, exposure of mice to ufCB induced an increased responsiveness to inhaled methacholine, and effect that was likewise inhibited by EGFR inhibitors. Thus, ufCB causes oxidative stress-mediated proliferation of airway smooth muscle and a resultant airway hyperreactivity, presumably through the processing of HB-EGF and EGF-R and ERK cascade activation.
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Report
(3 results)
Research Products
(10 results)
