大鼠之低甲狀腺素症與肝纖維化之相關

Abstract

肝纖維化是一個持續性的肝臟受損反應，病因可能由多種原因所造成，肝纖維化的形成是由於星狀細胞的活化，使之轉變為纖維母細胞樣，並且此過程中增加了膠原的合成以及減少其降解。Transforming growth factor beta (TGF-b)是一個多功能性的細胞激素，其可以調節受損之反應包括了纖維化的形成、生長的調節以及星狀細胞的凋亡等。之前的文獻已有對於低甲狀腺素症於動物模式中，用來防止肝纖維化的發展，但其中機制並未明瞭，因此，此篇文獻的目的主要在探討TGF-beta對於此一過程的作用。實驗選用30之成年雄性SD大鼠，以肝毒性藥物TAA進行腹腔注射，誘導其肝纖維化後，在進行分組給予低甲狀腺素誘導藥物，期間並測量AST，ALT，肝炎活性指數(Hepatitis activate index) 以及肝臟與體重之比值(liver weight/ body weight ratio)，TGF-beta和MMP之活性與濃度等。結果顯示肝臟酵素ALT，AST在以PTU所誘導的低甲狀腺素症組中，有達到顯著下降的情形，而HAI和肝臟與體重之比值也有改善的情形，此結果說明了藉由藥物所誘導的低甲狀腺素症可促進肝臟功能的回復。在TGF-beta的測定中，以PTU組別有達到顯著下降的情形，並且MMP-2的濃度只有輕微的下降，但是MMP-2與MMP-9的活性皆有顯著上升，推測可能是由於PTU所誘導的低甲狀腺素症，對於TGF-beta有急遽下降的情形，導致MMP-2分泌的量輕微的下降，並且其活性大量的上升，造成肝臟中膠原結締組織的降解，進而達到肝臟纖維化的回復情形。因此在低甲狀腺素症中低濃度的T4對於TGF-beta的下降是有其影響性的，這使得MMP的活性能夠大幅度的上升，而達到肝臟纖維化改善的狀況。

Liver fibrosis is the result of continuous liver injury stemming from different etiological factors. In the formation of liver fibrosis, the activated hepatic stellate cell (HSC) turn into myofibroblast cell, and this process increase synthesis of collagen and decrease degradation. Transforming growth factor beta (TGF-b) is a multifunctional cytokine, which regulate the injury response including fibrogenesis, growth regulation and HSC apoptosis. It has been shown in previous studies that hypothyroidism prevents the development of liver fibrosis in animal model, but the mechanism still unclear. Thus, in this study we investigated the effect of TGF-beta on the mechanism of collagen. Blood samples were collected from 30 rats, for the measurement of TGF-beta levels, the liver function value such as alanine aminogransferase (ALT), asparatate aminotransferase (AST), Hepatitis activate index (HAI) and liver weight/ body weight (L/B) ratio. The concentrations of AST (P<0.05) and ALT in the group of PTU treatment was declining in comparison another two groups. Both of L/B ratio and HAI in PTU-induced group were significantly (P<0.05) decreased compared to control and MMI-induced groups. TGF-beta level was significantly (P<0.05) decreased after PTU-treatment. The activity of MMP-9 was getting significantly (P<0.05) increased but not the amount of MMP-9. The level of hepatic fibrosis was degradation after 2 months PTU treatment in the rat with hepatic fibrosis induced by TAA. The low T4 concentration may inhibit the release of TGF-beta in PTU-induced group. The activity of MMP-9 was increased but not the total concentration of MMP-9 which indicated that MMP-9 activity is affected by TGF-beta and triggers the processing of degradation of hepatic fibrosis. Actually, in the group with hypothyroidism induced by PTU, the TGF-beta was significantly decreased but the activity of MMP-9 was increased. The decreased TGF-beta level may affect the activity of MMP-9 which can reverse the established hepatic fibrosis in rats. Therefore, we hypothesized that low level of T4 may decrease the release of TGF-beta which induced the activity of MMP-9 that have the benefit on the reverse of established hepatic fibrosis in rats.