Iimuro Yuji, Nishio Toshihiro, Morimoto Taisuke, Nitta Takashi, Stefanovic Branko, Choi Sung Kyu, Brenner David A, Yamaoka Yoshio
Department of Gastroenterological Surgery, Kyoto University Graduate School of Medicine, Japan.
Gastroenterology. 2003 Feb;124(2):445-58. doi: 10.1053/gast.2003.50063.
BACKGROUND & AIMS: During hepatic fibrogenesis, the hepatic extracellular matrix changes to fibrillar collagens types I and III, and cirrhosis is believed to produce an irreversible scar. In this study, we investigated whether gene delivery of human matrix metalloproteinase-1, which degrades collagens types I and type III, would attenuate established hepatic fibrosis in the rat, induced by either thioacetamide or bile duct ligation.
Hepatic fibrosis induced by thioacetamide for 7 weeks was persistent for at least 2 months, even after discontinuation of the treatment. The rats were infected once with a recombinant adenovirus, Ad5MMP-1, into which human pro-human matrix metalloproteinase-1 complementary DNA was packaged, or with a control adenovirus, Ad5LacZ.
In Ad5MMP-1-infected, but not in Ad5LacZ-infected, rats, the fibrosis was dramatically attenuated at 2 weeks after the infection. It is interesting to note that the number of activated hepatic stellate cells was also decreased in Ad5MMP-1-infected rats. Moreover, disorganization of the hepatic trabecula, heterogeneity in the size of hepatocytes, and increased dried liver weight were observed only in Ad5MMP-1-treated rats, suggesting that human matrix metalloproteinase-1 stimulated hepatocyte proliferation, which was confirmed by bromodeoxyuridine staining. After 4 weeks, the proliferative effect of human matrix metalloproteinase-1 almost disappeared, but the hepatic fibrosis remained attenuated, whereas the fibrosis in Ad5LacZ-treated rats persisted. Furthermore, the administration of Ad5MMP-1, but not Ad5LacZ, decreased type I collagen and generated a small collagen fragment in hepatic fibrosis induced by bile duct ligation.
Our findings show that transient human matrix metalloproteinase-1 overexpression in the liver effectively attenuates established fibrosis and induces hepatocyte proliferation.
在肝纤维化形成过程中，肝脏细胞外基质转变为I型和III型纤维状胶原蛋白，并且肝硬化被认为会产生不可逆的瘢痕。在本研究中，我们调查了递送可降解I型和III型胶原蛋白的人基质金属蛋白酶-1基因是否会减轻大鼠由硫代乙酰胺或胆管结扎诱导的已形成的肝纤维化。
硫代乙酰胺诱导的肝纤维化持续7周，即使在停止治疗后至少持续2个月。大鼠一次性感染包装有人前体人基质金属蛋白酶-1互补DNA的重组腺病毒Ad5MMP-1，或对照腺病毒Ad5LacZ。
在感染Ad5MMP-1而非Ad5LacZ的大鼠中，感染后2周纤维化显著减轻。有趣的是，在感染Ad5MMP-1的大鼠中，活化的肝星状细胞数量也减少。此外，仅在接受Ad5MMP-1治疗的大鼠中观察到肝小梁紊乱、肝细胞大小不均一以及肝干重增加，提示人基质金属蛋白酶-1刺激了肝细胞增殖，这通过溴脱氧尿苷染色得到证实。4周后，人基质金属蛋白酶-1的增殖作用几乎消失，但肝纤维化仍减轻，而Ad5LacZ治疗的大鼠中的纤维化持续存在。此外，给予Ad5MMP-1而非Ad5LacZ可减少胆管结扎诱导的肝纤维化中的I型胶原蛋白并产生小的胶原蛋白片段。
我们的研究结果表明，肝脏中短暂的人基质金属蛋白酶-1过表达可有效减轻已形成的纤维化并诱导肝细胞增殖。
