Bruck R, Hershkoviz R, Lider O, Shirin H, Aeed H, Halpern Z
Department of Gastroenterology, E. Wolfson Medical Center, Holon, Israel.
Yale J Biol Med. 1997 Jul-Aug;70(4):391-402.
In chronic viral hepatitis, autoimmune hepatitis, and some chronic cholestatic liver diseases, T-lymphocytes serve as effector cells of the immunostimulatory processes. Cellular interactions of immune cells with extracellular matrix (ECM) components are regulated primarily via the beta 1 subfamily of integrin receptors. The target epitope of several such integrin receptors is the Arg-Gly-Asp (RGD) sequence, a cell adhesion motif shared by several matrix-associated adhesive glycoproteins. We review the use of synthetic nonpeptidic analogues of RGD and of soluble receptor of tumor necrosis factor (TNF)-alpha in the prevention of immune-mediated, concanavalin A-induced liver damage in mice and of RGD analogues in inhibiting the development of liver cirrhosis in rats. The concanavalin A-induced elevation of serum transaminases and TNF-alpha, and the infiltration of liver tissue by inflammatory cells, were inhibited by pretreatment of the mice with the synthetic RGD mimetics and soluble TNF receptor. In rats, the progression of thioacetamide-induced liver cirrhosis was markedly inhibited by the coadministration of the RGD mimetic SF-6,5. The compounds described here may be examined therapeutically for pathological conditions in the liver, manifested as necroinflammation, cholestasis and fibrosis.
在慢性病毒性肝炎、自身免疫性肝炎和一些慢性胆汁淤积性肝病中，T淋巴细胞作为免疫刺激过程的效应细胞。免疫细胞与细胞外基质（ECM）成分的细胞相互作用主要通过整合素受体的β1亚家族进行调节。几种此类整合素受体的靶表位是精氨酸-甘氨酸-天冬氨酸（RGD）序列，这是几种与基质相关的粘附糖蛋白共有的细胞粘附基序。我们综述了RGD的合成非肽类似物和肿瘤坏死因子（TNF）-α可溶性受体在预防小鼠免疫介导的刀豆蛋白A诱导的肝损伤中的应用，以及RGD类似物在抑制大鼠肝硬化发展中的应用。刀豆蛋白A诱导的血清转氨酶和TNF-α升高以及炎症细胞对肝组织的浸润，通过用合成RGD模拟物和可溶性TNF受体预处理小鼠而受到抑制。在大鼠中，硫代乙酰胺诱导的肝硬化进程通过联合给予RGD模拟物SF-6,5而受到显著抑制。本文所述的化合物可用于治疗肝脏中表现为坏死性炎症、胆汁淤积和纤维化的病理状况。
