| Project/Area Number |
17590795
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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 | Nagasaki University |
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Principal Investigator |
MUKAE Hiroshi Nagasaki University, Graduate School of Biomedical Sciences, Research Associate, 大学院医歯薬学総合研究科, 講師 (80253821)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | Heat shock protein / Idiopathic pulmonary fibrosis / defensins / collagen / type II pneumocytes / lung fibroblasts / Heat shock protein 47 / 突発性肺線維症 / II型肺胞上皮細胞 / 特発性肺線維症 |
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| Research Abstract |
Heat shock Protein (HSP) 47 is involved in the synthesis/assembly of various collagens as a collagen-Specific molecular chaperone. HSP 47 expression has been shown upregulated in liver cirrhosis and other fibrotic diseases. We have studied the effect of α-defensin, cationic proteins with antimicrobial and cytotoxic activity in the azurophil granule of neutrophils, on the production of HSP 47 and collagen using lung fibroblasts, and the relationship between HSP47 expression and fibrotic process in murine bleomycin-induced pulmonary fibrosis. At first, using surgical biopsy specimens from human patients, we demonstrated that expression of HSP47 in lung fibroblasts and type II pneumocytes was significantly higher in idiopathic usual interstitial pneumonia (UIP) patients than in those with collagen vascular disease-associated UIP and idiopathic non-specific interstitial pneumonia, which has the better prognosis compared with idiopathic UIP. We also investigated the direct effect of α-defen
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sin (human neutrophil peptide (HNP)-1) on expression of HSP47 and collagen-1 in human lung fibroblasts. HNP-1 5 μg/ml induced fibroblast proliferatioh and concentrations >50 μg/ml of HNP-1 reduced the cell-viability. Expression of HSP 47 and collagen-1 mRNA was significantly increased by 10 to 25 μg/ml of HNP-1, whereas their protein release increased in dose-dependent manner. TGF-beta also enhanced the expression of these mRNA and proteins in human normal fibroblasts and A549 cells, and pirfenidone inhibited these findings. In addition, We are studying the effects of TGF-beta on expression of growth factors including PDGF and HGF in A549 and fibroblasts using real time PCR. In murine bleomycin-induced pulmonary fibrosis, a good correlation was also observed between the degree of pulmonary fibrosis and expression of HSP47 using in situ hybridization. Our results suggest that α-defensin may promote directly fibrotic process through upregulation of HSP 47 and collagen-1 in human lung fibroblasts and play an important role in the pathogenesis of pulmonary fibrosis and HSP47 positive cells may have an ability of enhanced collagen synthesis and release. Pirfenidone inhibited directly these positive cells responsible for the accumulation and deposition of extracellular matrix seen in pulmonary fibrosis. These findings suggest that BSP47 and α-defensin might be anew promising target for the treatment of idiopathic pulmonary fibrosis. Less
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