| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1996: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1995: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1994: ¥800,000 (Direct Cost: ¥800,000)
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| Research Abstract |
Tissue inhibitor of metalloproteinases (TIMP) -1 is an important regulator of matrix metalloproteinase activity. Recently, we have demonstrated that the serum levels of TIMP-1 are increased in patients with chronic active liver disease, correlating with the histological degree of liver fibrosis. To clarify the changes in TIMP-1 in diseased livers, we measured TIMP-1 concentrations in liver tissue samples from patients with chronic liver disease. We carried out an immunohistochemical staining for TIMP-1. The relationship between serum and liver levels of TIMP-1 was examined in some patients. As compared with the controls, the mean liver TIMP-1 level was increased 2.2-fold in chronic active hepatitis 2A patients, 2.9-fold in chronic active hepatitis 2B patients and 4.1-fold in liver cirrhosis patients, but no significant increase was observed among chronic persistent hepatitis patients. The liver TIMP-1 levels were closely correlated with the histological degrees of periportal necrosis,
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portal inflammation, and liver fibrosis. When the localization of TIMP-1 was examined immunohistochemically, TIMP-1 was stained mainly in hepatocytes, and the intensity was stronger in the livers of chronic active hepatitis and liver cirrhosis patients than in those of the chronic persistent hepatitis patients. The serum TIMP-1 and liver TIMP-1 levels were significantly correlated, indicating that serum TIMP-1 could reflect the change of liver TIMP-1 in patients with chronic liver disease. Gelfiltrattion of liver extract and plasma showed that the major peak of TIMP-1 in both samples was eluted at around 40 kDa, indicating that TIMP-1 is present as TIMP-1 complexed with a small protein which is probably a fragment of MMP.Transforming growth factor (TGF) -beta1 is an important cytokine involved in the production of TIMP-1. Plasma TGF-beta1 levels were positively correlated with blood levels of TIMP-1
In conclusion, the liver TIMP-1 concentration increased with the progress of liver disease, where the degradation of extracellular matrix proteins is decreased, resulting in the development of liver fibrosis. Less
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