The study of synthesis and degradation of extracellular collagen matrix in disease animal models

博士 === 國立中興大學 === 獸醫學系暨研究所 === 98 === Extracellular collagen matrix (ECM), defined as an intricate network of macromolecules that is a member of the collagen glycoprotein family, is the predominant proteins of connective tissues existed in most organs on a wide range. ECM plays an integral role in r...

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Main Authors: Ching-Chang Cheng, 程景章
Other Authors: Kwong-Chung Tung
Format: Others
Language:zh-TW
Published: 2010
Online Access:http://ndltd.ncl.edu.tw/handle/98739147338763497262
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spelling ndltd-TW-098NCHU55410102015-10-30T04:05:02Z http://ndltd.ncl.edu.tw/handle/98739147338763497262 The study of synthesis and degradation of extracellular collagen matrix in disease animal models 以疾病動物模式研究細胞外膠原母質之消長 Ching-Chang Cheng 程景章 博士 國立中興大學 獸醫學系暨研究所 98 Extracellular collagen matrix (ECM), defined as an intricate network of macromolecules that is a member of the collagen glycoprotein family, is the predominant proteins of connective tissues existed in most organs on a wide range. ECM plays an integral role in regulating cell function, differentiation and tissue-specific gene expression and is essential for maintaining the structure and function of tissue during development, tissue remodeling and repair processes. Fibroblasts are named variably such as hepatic stellate cells (HSCs) in Disse’s space of liver and the surface markers and gene expression of them were also heterogenious in different organs. In the myocardium, ECM was essentially possessed in the homeostasis stage to maintain the mechanical and physicochemical properties in heart pump function. However fibrogenesis is the outcome of hepatic repair in liver injuries. During liver fibrogenesis caused by abnormal accumulation of ECM, especially collagens type I and III, HSCs undergo activation which is a process characterized by morphological transformation into myofibroblast-like cells and synthesis of excessive ECM components. Disruption of ECM homeostasis is also a deciding factor for the progression of disease. Matrix metalloproteinases (MMPs) were calcium-dependent ECM-degrading proteases. Increase levels of MMPs activity can promote degradation of normal matrix proteins and ECM remodeling that result in dysfunction or failure in the organs. In this study, we investigated the role of MMPs and ECM in the pathogenesis of acute heart failure and chronic liver fibrosis by neurocardiogenic injury and CCl4-induced liver fibrosis animal models. In neurocardiogenic injury, sympathetic hyperactivation was induced by electrical stimulation of dorsal medulla (ESDM) of brain stem. ESDM caused hyperexitation of norepinephrin in plasma, tachycardia, hypertension, dilation of LV chamber, poor ejection fraction and ventricular dysfunction. Acute heart failure resulted in raise of myocardial MMPs level which accelerates disruption and fragmentation of cardiac ECM (epimysial weaves, perimysial coils and endomysial struts). In chronic liver fibrosis model, Shugan-huayu powder (SHP) not only improved hepatic function as decreased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) but also revealed antifibrotic effect throught inhibiting activation, proliferation and MMPs expression of HSCs. Combine therapy of Salvia miltiorrhiza (SM) and rapamycin (Rapa) enhanced the mortality to 50%, even though, MMP-2 activity and numbers of active HSCs were attenuated in anti-liver fibrotic study of herb drugs combining with western medicine. However, the toxity and side effect in Rapa, Rapa+SM was more severe than SHP and Rapa+SHP. In conclusion, attenuated the MMPs activity of fibroblast or myofibroblast (active fibroblast) will modify ECM synthesis or degradation in the interstitial space. These changes may lead to ECM remodeling even or reverse to normal altitude. The ESDM result in acute heart model and CCl4-induced liver fibrosis model will be prominent in ECM remodeling and anti-MMPs development of human beings. Kwong-Chung Tung 董光中 2010 學位論文 ; thesis 87 zh-TW
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description 博士 === 國立中興大學 === 獸醫學系暨研究所 === 98 === Extracellular collagen matrix (ECM), defined as an intricate network of macromolecules that is a member of the collagen glycoprotein family, is the predominant proteins of connective tissues existed in most organs on a wide range. ECM plays an integral role in regulating cell function, differentiation and tissue-specific gene expression and is essential for maintaining the structure and function of tissue during development, tissue remodeling and repair processes. Fibroblasts are named variably such as hepatic stellate cells (HSCs) in Disse’s space of liver and the surface markers and gene expression of them were also heterogenious in different organs. In the myocardium, ECM was essentially possessed in the homeostasis stage to maintain the mechanical and physicochemical properties in heart pump function. However fibrogenesis is the outcome of hepatic repair in liver injuries. During liver fibrogenesis caused by abnormal accumulation of ECM, especially collagens type I and III, HSCs undergo activation which is a process characterized by morphological transformation into myofibroblast-like cells and synthesis of excessive ECM components. Disruption of ECM homeostasis is also a deciding factor for the progression of disease. Matrix metalloproteinases (MMPs) were calcium-dependent ECM-degrading proteases. Increase levels of MMPs activity can promote degradation of normal matrix proteins and ECM remodeling that result in dysfunction or failure in the organs. In this study, we investigated the role of MMPs and ECM in the pathogenesis of acute heart failure and chronic liver fibrosis by neurocardiogenic injury and CCl4-induced liver fibrosis animal models. In neurocardiogenic injury, sympathetic hyperactivation was induced by electrical stimulation of dorsal medulla (ESDM) of brain stem. ESDM caused hyperexitation of norepinephrin in plasma, tachycardia, hypertension, dilation of LV chamber, poor ejection fraction and ventricular dysfunction. Acute heart failure resulted in raise of myocardial MMPs level which accelerates disruption and fragmentation of cardiac ECM (epimysial weaves, perimysial coils and endomysial struts). In chronic liver fibrosis model, Shugan-huayu powder (SHP) not only improved hepatic function as decreased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) but also revealed antifibrotic effect throught inhibiting activation, proliferation and MMPs expression of HSCs. Combine therapy of Salvia miltiorrhiza (SM) and rapamycin (Rapa) enhanced the mortality to 50%, even though, MMP-2 activity and numbers of active HSCs were attenuated in anti-liver fibrotic study of herb drugs combining with western medicine. However, the toxity and side effect in Rapa, Rapa+SM was more severe than SHP and Rapa+SHP. In conclusion, attenuated the MMPs activity of fibroblast or myofibroblast (active fibroblast) will modify ECM synthesis or degradation in the interstitial space. These changes may lead to ECM remodeling even or reverse to normal altitude. The ESDM result in acute heart model and CCl4-induced liver fibrosis model will be prominent in ECM remodeling and anti-MMPs development of human beings.
author2 Kwong-Chung Tung
author_facet Kwong-Chung Tung
Ching-Chang Cheng
程景章
author Ching-Chang Cheng
程景章
spellingShingle Ching-Chang Cheng
程景章
The study of synthesis and degradation of extracellular collagen matrix in disease animal models
author_sort Ching-Chang Cheng
title The study of synthesis and degradation of extracellular collagen matrix in disease animal models
title_short The study of synthesis and degradation of extracellular collagen matrix in disease animal models
title_full The study of synthesis and degradation of extracellular collagen matrix in disease animal models
title_fullStr The study of synthesis and degradation of extracellular collagen matrix in disease animal models
title_full_unstemmed The study of synthesis and degradation of extracellular collagen matrix in disease animal models
title_sort study of synthesis and degradation of extracellular collagen matrix in disease animal models
publishDate 2010
url http://ndltd.ncl.edu.tw/handle/98739147338763497262
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