Regeneration of injured intestinal mucosa is impaired in hepatocyte growth factor activator-deficient mice
Regeneration of injured intestinal mucosa is impaired in hepatocyte growth factor activator-deficient mice
复制标题
DOI：
10.1053/j.gastro.2004.08.027
复制
发表时间：
2004-11-01
期刊：
影响因子：
29.4
通讯作者：
Kataoka, H
中科院分区：
文献类型：
--
作者：
Itoh, H;Naganuma, S;Kataoka, H
背景与目的：肝细胞生长因子激活剂(HGFA)是一种血清蛋白水解酶，能特异性地将失活的单链肝细胞生长因子(HGF)转化为活性的2链肝细胞生长因子(HGF)。HGFA以其前体形式产生，然后在受损组织中被激活。为了解决HGFA的确切作用和研究HGF在损伤组织中的激活机制，我们产生了HGFA缺陷的小鼠。方法：采用靶向基因阻断的方法建立HGFA基因缺陷小鼠模型。观察了口服葡聚糖硫酸钠(DSS)和直肠注射醋酸对HGFA基因缺陷小鼠肠黏膜损伤的再生过程。用Western blotting和HGF激活实验分析HGF的加工活性。结果：纯合子突变小鼠存活并能生育，无明显异常。在饮水中加入3%的DSS 6天后，不加DSS的蒸馏水处理HGFA基因缺陷小鼠，12天后72%的小鼠死亡，而对照组小鼠损伤后存活75%。在醋酸诱导的肠道损伤中也观察到类似的结果，HGFA缺陷小鼠的存活率为36.6%，对照组小鼠的存活率为84.2%。在HGFA基因缺陷小鼠中，损伤的粘膜没有被再生的上皮充分覆盖，损伤的结肠中HGF的激活受到损害。结论：hGFA对损伤肠粘膜的修复是必需的，但对胚胎发育和出生后的正常发育不是必需的。
Background & Aims: Hepatocyte growth factor activator (HGFA) is a serum proteinase that specifically converts an inactive single-chain form of hepatocyte growth factor (HGF) into an active 2-chain form. HGFA is produced in its precursor form and then activated in injured tissues. To address the precise role of HGFA and to investigate the mechanisms of HGF activation in injured tissues, we generated mice deficient in HGFA. Methods: HGFA-deficient mice were generated using targeted gene disruption. The regenerating process of intestinal mucosa damaged by oral administration of dextran sodium sulfate (DSS) or by rectal administration of acetic acid was examined in both HGFA-deficient and control mice. HGF processing activity was analyzed using Western blotting and an HGF activation assay. Results: Homozygous mutant mice were viable and fertile without obvious abnormalities. When mice were treated with 3% DSS in drinking water for 6 days followed by distilled water without DSS, 72% of HGFA-deficient mice died through day 12 while 75% of control mice survived injury. Similar results were also observed in the acetic acid-induced intestinal injury; the survival rate was 36.6% in HGFA-deficient mice and 84.2% in control mice. In HGFA-deficient mice, the injured mucosa was not sufficiently covered by regenerated epithelium and the activation of HGF was impaired in the injured colon. Conclusions: These results indicate that HGFA is required for repair of injured intestinal mucosa but is not essential for normal development during embryogenesis or after birth.