Molecular and cellular biological analyzes of morphogenesis modulated by HGF

1.含酒精饲料喂养37天后，大鼠肝脏脂质显著增加，肝细胞内脂滴聚集，提示酒精性脂肪肝的发生。结论：1.乙醇处理后7天给予肝细胞生长因子(HGF)可明显降低肝脂水平，降至治疗前水平。在二甲基亚硝胺诱导的致死性肝硬变大鼠模型中，重复将人HGF基因导入骨骼肌，可诱导人和内源性大鼠HGF水平升高，c-Met/HGR受体酪氨酸磷酸化。转导HGF基因还可抑制肝纤维化形成和肝细胞凋亡，使肝硬变纤维化完全消退，从而提高重症大鼠的存活率。这些小鼠是慢性肾脏疾病的自发小鼠模型(ICGN品系)，逐渐发展为肾小球…硬化性损伤、肾小管萎缩和肾功能不全持续到17wk。在自发性慢性肾脏疾病小鼠模型(ICGN株)中，给予HGF 4-wk周期(从14-17周)可防止肾功能障碍和纤维化的进展。HGF在培养的心肌细胞和心肌内皮细胞中产生，在再灌流心肌梗死的存活边缘区域产生。与生理盐水治疗相比，HGF和HGF基因治疗可显著减少大鼠再灌流后心肌损伤的心肌梗死面积和细胞凋亡数。HGF对谷氨酸诱导的大脑皮层神经细胞有保护作用。微量泵持续脑室注射HGF减轻急性脑缺血模型大鼠大脑皮层迟发性神经细胞死亡。HGF/NK4在体内和体外均能抑制肿瘤的侵袭，HGF/NK4还竞争性抑制Gb-D1人胆囊癌细胞上HGF与Met/HGF受体的结合，增加Ge-d1移植瘤细胞的凋亡，抑制肿瘤的体内生长。除了对HGF的拮抗作用外，HGF/NK4在体内外均能抑制成纤维细胞生长因子、血管内皮生长因子和肝细胞生长因子诱导的血管生成，减少肿瘤的生长体积和血管生成，提示HGF在肿瘤生长和侵袭中具有潜在的作用。较少

1. Rats fed ethanol-containing diets for 37 days showed remarkable increase in hepatic lipids and lipid droplet accumulation in the hepatocytes, indicating the onset of alcholic fatty liver. Administration of hepatocyte growth factor (HGF) for the last seven days of ethanol treatment markedly decreased hepatic lipids to the level lower than that seen before HGF treatment.2. In a rat model of lethal liver cirrhosis produced by dimethylnitrosamine administrations, repeated transfections of the human HGF gene into skeletal muscles induced ahigh plasmalevel of human as well as endogeneous rat HGF, and tyrosine phosphorylation of the c-Met/HGR receptor. Transduction with the HGF gene also inhibited fibrogenesis and hepatocyte appoptosis, and produced the complete resolution of fibrosis in the cirrhotic liver, thereby improving the survival rate of rats with this severe illness.3. The mice, a spontaneous mouse model for chronic renal disease (ICGN strain), progressively developed glomerular … More sclerotic injury, tubular atrophy and renal disfunction until they were 17 wk of age. Administration of HGF for 4-wk-periods(from weeks 14-17) prevented the progression of renal dysfunction and fibrosis in a spontaneous mouse model for chronic renal disease (ICGN strain).4. HGF was produced in cardiomyocytes and cardiac endothelial cells in culture, and in viable border zone of reperfused myocardiac infarction. Administration of HGF and HGF gene markedly decreased infarct area and apoptotic cradiac cell death in rat postreperfusion myocardial injury, compared with saline treatment.5. HGF prevented cerebral corteical neuronal cell induced by glutamate.6. Continuous intra-ventricular administration of HGF by mini-pump attenuated delayed neuronal cell death of cerebral cortex in acute brain ischemic model.7. We have previously demonstrated a four-kringle-containing fragment of HGF, HGF/NK4 inhibits invasion of tumors in vivo, as well as in vitro, and HGF/NK4 also competitively inhibited the binding of HGF to Met/HGF receptor on GB-d1 human gallbladder carcinoma cells, increased apoptosis of implanted GE-d1 apoptotic cell death and inhibited this tumor growth in vivo. In addition to the antagonistic activity against HGF, HGF/NK4 inhibited angiogenesis induced by FGF, VEGF and HGF in vitro and in vivo, and decreased growth size and angiogenesis of tumors, such as Luwis lung cancer cells, suggesting bipotential role of HGF for tumor grwoth and invasion. Less