| Project/Area Number |
16590747
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Respiratory organ internal medicine
|
|---|
| Research Institution | Hiroshima University |
|---|
Principal Investigator |
YOKOYAMA Akihito Hiroshima University, Graduate School of Biomedical Sciences, Associate Professor, 大学院・医歯薬学総合研究科, 助教授 (30191513)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
KOHNO Nobuoki Graduate School of Biomedical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (80215194)
近藤 圭一 島根大学, 医学部附属病院, 講師 (20332827)
|
|---|
| Project Period (FY) |
2004 – 2006
|
| Project Status |
Completed (Fiscal Year 2006)
|
| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2005: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
|
|---|
| Keywords | bronchial asthma / cytokine / fibroblast / T cells / interferon / pulmonary fibrosis / remodeling |
|---|
| Research Abstract |
The purpose of this study is to disclose the mechanisms of airway and lung parenchymal fibrosis. We specifically explore the roles of T cells and a negative regulator of cytokine signaling, suppressor of cytokine signaling-1 (SOCS-1) in the regulatory mechanisms of lung fibrosis.
(1) By using polarized Th1 and Th2 cells from TCR-transgenic mice, we demonstrated that activation of Th1 cells followed by Th2 cells in the lung can induce lung fibrosis in vivo.
(2) To investigate the characteristics of fibroblasts in idiopathic pulmonary fibrosis (IPF), we obtained 8 fibroblast cell lines from lungs with IPF and 8 lines from normal lungs. We found that the fibroblasts from IPF spontaneously produced higher amounts of type I collagen and had lower expression levels of SOCS1 than fibroblasts from normal lung. Following IFN-γ stimulation, the amount of SOCS1 mRNA expressed by IPF fibroblasts was comparable to that of normal fibroblasts. Thus, the extent of SOCS1 increase after stimulation by IFN
… More
-γ was significantly higher in IPF fibroblasts. The extent to which IFN-γ inhibited collagen production was also larger in IPF fibroblasts than in normal fibroblasts.
(3) By using mouse fibroblasts, we demonstrated the causal relationship between decreased expression of SOCS-1 and increased production of collagen: the deficiency of SOCS1 in fibroblasts resulted in increased collagen production, whereas overexpression of SOCS1 suppressed collagen production. IFN-γ suppressed spontaneous collagen production even in SOCS1-deficient fibroblasts, indicating that IFN-γ inhibition is SOCS1-independent. In contrast, IFN-γ suppressed the increase of collagen production induced by IL-4 in wild type fibroblasts but not SOCS1-deficient fibroblasts, suggesting IFN-γ acted exclusively via SOCS1 in this case.
(4) These results suggest that the exaggerated production of collagen observed in fibroblasts from IPF is causally related to the diminished expression of SOCS1, and IPF fibroblasts are more susceptible to IFN-γ because of decreased expression of SOCS1. Less
|
