肝细胞生长因子与神经系统疾病

肝细胞生长因子是一种对神经系统有较强营养作用的细胞因子,对中枢和周围神经元的生长、分化、修复和再生起重要作用。近年来的研究表明,肝细胞生长因子与多种神经系统疾病,如脑缺血、运动神经元病、神经胶质瘤、Alzheimer病等的发生发展密切相关。文章综述了肝细胞生长因子在神经系统疾病中的表达和作用。     

肝细胞生长因子与神经系统疾病

肝细胞生长因子是一种对神经系统有较强营养作用的细胞因子，对中枢和周围神经元的生长、分化、修复和再生起重要作用。近年来的研究表明，肝细胞生长因子与多种神经系统疾病，如脑缺血、运动神经元病、神经胶质瘤、Alzheimer病等的发生发展密切相关。文章综述了肝细胞生长因子在神经系统疾病中的表达和作用。     

用流式细胞计检测表皮生长因子对肝细胞DNA合成的刺激作用

用流式细胞术和单克隆抗溴脱氧脲嘧啶抗体标记 DNA 技术检测了表皮生长因子、胰高血糖素和胰岛素对大鼠初代培养肝细胞 DNA 合成的刺激作用。结果表明表皮生长因子对肝细胞DNA 合成具有明显的增强作用,并且这种作用可以被胰岛素进一步加强。当表皮生长因子、胰岛素和胰高血糖素三者联合使用时,肝细胞 DNA 合成显著增强。提示表皮生长因子,特别是它与胰岛素和胰高血糖素联合使用可以明显刺激肝细胞的再生。     

细胞因子

1.与肝脏再生相关的细胞因子:现发现在肝再生时,成纤维细胞生长因子(FGF)、表皮生长因子(EGF)、转化生长因子α(TGFα)、和肝细胞生长因子(HGF)对肝细胞的DNA合成可能起生理上的诱导因子作用。它们通过自身分泌和旁分泌机制起作用。转化生长因子β使EGF和TG     

肝细胞生长因子与缺血性脑血管病

肝细胞生长因子是一种对神经系统有较强营养作用的细胞因子，对中枢和周围神经元的发育、生长、分化、修复和再生中起重要作用，现已成为神经科学领域的研究热点。文章综述了肝细胞生长因子及其受体在脑缺血后的表达和作用。     

肝细胞生长因子对糖基化终产物诱导内皮细胞凋亡的影响

目的探讨糖基化终产物对内皮细胞的凋亡作用,以及肝细胞生长因子对内皮细胞凋亡的影响。方法体外培养人脐静脉内皮细胞,予不同浓度糖基化终产物及肝细胞生长因子干预,分为实验对照组及100 mg/L、200mg/L4、00 mg/L糖基化终产物组和400 mg/L糖基化终产物 100μg/L肝细胞生长因子组,采用四甲基偶氮唑蓝比色法测定各组内皮细胞生长抑制率,通过吖啶橙荧光染色观察细胞形态学变化,流式细胞术测定Annexin V-FITC/PI双染标记的细胞凋亡率,检测肝细胞生长因子对糖基化终产物诱导内皮细胞凋亡的影响;蛋白免疫印迹法分析各组凋亡基因Bax、Bcl-2蛋白的表达及酶联反应法测定细胞凋亡蛋白酶3的活性。结果肝细胞生长因子能明显降低糖基化终产物对内皮细胞生长的抑制作用(P<0.01);糖基化终产物诱导培养的内皮细胞出现明显的凋亡形态学改变,在一定浓度范围内,内皮细胞凋亡率与糖基化终产物的浓度和作用时间呈依赖关系,肝细胞生长因子干预后可显著降低不同时间的内皮细胞凋亡率(P<0.05);肝细胞生长因子作用内皮细胞抗凋亡基因Bcl-2表达明显升高(P<0.01),而促凋亡基因Bax表达无明显变化(P>0.05);细胞凋亡蛋白酶3活性显著降低(P<0.05)。结论糖基化终产物诱导人内皮细胞凋亡,而肝细胞生长因子抑制糖基化终产物诱导的内皮细胞凋亡,其作用机制可能是上调抗凋亡基因Bcl-2水平、抑制细胞凋亡蛋白酶3的激活。     

肝细胞生长因子在心血管疾病中的研究

肝细胞生长因子是一种多功能的细胞因子,具有多种生物学活性,包括促有丝分裂、细胞移动、形态学发生和血管形成、抗细胞凋亡、抗纤维化等,对心血管具有重要的保护作用。本文就近年肝细胞生长因子在心血管疾病中的应用做一综述。     

肝细胞生长因子与消化系统疾病

肝细胞生长因子是具有多种生物学功能的细胞因子,近年来人们对它在组织损伤修复及在肿瘤发展进程中的作用越来越重视。本文对肝细胞生长因子与消化系统疾病关系的研究进展作一综述。     

阿霉素致大鼠肝细胞凋亡及亚硒酸钠的保护作用

目的　探讨阿霉素对肝细胞的损伤机制及亚硒酸钠对肝细胞的保护作用。方法　通过复制大鼠阿霉素性心肌损伤的动物模型,以亚硒酸钠作为保护因素,应用原位末端标记法（ Ｔ Ｕ Ｎ Ｅ Ｌ）和免疫组化技术检测大鼠肝细胞凋亡和肝细胞转化生长因子 β１ 表达,并观察了大鼠血清中脂质过氧化含量。结果　阿霉素组大鼠肝组织可见细胞凋亡和肝细胞中转化生长因子 β１ 的异常表达;阿霉素组大鼠血清中脂质过氧化物明显升高;亚硒酸钠对阿霉素的损伤有明显的保护作用。结论　阿霉素诱导肝细胞凋亡可能是其肝脏损伤机制之一,并且细胞凋亡与转化生长因子 β１的高表达和血清中脂质过氧化水平升高有密切关系。     

肝细胞生长因子在心血管疾病中的研究

肝细胞生长因子是一种多功能的细胞因子,具有多种生物学活性,包括促有丝分裂、细胞移动、形态学发生和血管形成、抗细胞凋亡、抗纤维化等,对心血管具有重要的保护作用.本文就近年肝细胞生长因子在心血管疾病中的应用做一综述.     

Hepatocyte growth factor, its receptor, and their potential value in cancer therapies

Hepatocyte growth factor plays multiple roles in cancer, by acting as a motility and invasion stimulating factor, promoting metastasis and tumour growth. Furthermore, it acts as a powerful angiogenic factor. The pivotal role of this factor in cancer has indicated HGF as being a potential target in cancer therapies. The past few years have seen rapid progress in developing tools in targeting HGF, in the context of cancer therapies, including development of antagonists, small compounds, antibodies and genetic approaches. The current article discusses the potential value of HGF and its receptor as targets in cancer therapies, the current development in anti-HGF research, and the clinical value of HGF in prognosis and treatment.     

Autocrine interactions of keratinocyte growth factor, hepatocyte growth factor, and kit-ligand in the regulation of normal ovarian surface epithelial cells

Ovarian tumors are primarily derived from the layer of epithelium surrounding the ovary termed the ovarian surface epithelium (OSE). Although extensive research has focused on established ovarian tumors, relatively little is known about the normal biology of the OSE that gives rise to ovarian cancer. The local expression and actions of growth factors are likely involved in both normal and tumorigenic OSE biology. The current study investigates the expression and action of keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), and kit-ligand (KL) in normal ovarian surface epithelium (OSE). The actions of various growth factors on KGF, HGF, and KL expression are examined. Observations indicate that freshly isolated normal OSE express the genes for KGF, HGF, and KL and expression is maintained in vitro. KGF messenger RNA expression in OSE was found to be stimulated by KGF and HGF, but not KL. HGF expression in OSE was found to be stimulated by KGF, HGF, and KL. KL expression in OSE was also found to be stimulated by KGF, HGF, and KL. Therefore, the various growth factors can regulate the mRNA expression of each other in OSE. Effects of growth factors on OSE growth were examined. KGF, HGF, and KL stimulated OSE growth to similar levels as the positive control epidermal growth factor. Observations suggest that KGF, HGF, and KL interact to promote OSE growth and growth factor expression. The ability of these growth factors to interact in a positive autocrine feedback loop is postulated to be important for normal OSE biology. Paracrine interactions with the adjacent stromal cells will also be a factor in OSE biology. Abnormal interactions of these growth factors may be involved in the onset and progression of ovarian cancer.     

Hepatocyte growth factor twenty years on: Much more than a growth factor

Liver regeneration depends on the proliferation of mature hepatocytes. In the 1980s, the method for the cultivation of mature hepatocytes provided an opportunity for the discovery of hepatocyte growth factor (HGF) as a protein that is structurally and functionally different from other growth factors. In 1991, the scatter factor, tumor cytotoxic factor, and 3-D epithelial morphogen were identified as HGF, and Met tyrosine kinase was identified as the receptor for HGF. Thus, the connection of apparently unrelated research projects rapidly enriched the research on HGF in different fields. The HGF-Met pathway plays important roles in the embryonic development of the liver and the placenta, in the migration of myogenic precursor cells, and in epithelial morphogenesis. The use of tissue-specific knockout mice demonstrated that in mature tissues the HGF-Met pathway plays a critical role in tissue protection and regeneration, and in providing less susceptibility to chronic inflammation and fibrosis. In various injury and disease models, HGF promotes cell survival, regeneration of tissues, and suppresses and improves chronic inflammation and fibrosis. Drug development using HGF has been challenging, but extensive preclinical studies to address its therapeutic effects have provided significant results sufficient for the development of HGF as a biological drug in the regeneration-based therapy of diseases. Clinical trials using recombinant human HGF protein, or HGF genes, are in progress for the treatment of diseases.     

Translational research to identify clinical applications of hepatocyte growth factor

Hepatocyte growth factor (HGF), originally purified from the plasma of patients with fulminant hepatic failure, has been shown to carry out various physiological functions. HGF not only stimulates liver regeneration, but also acts as an antiapoptotic factor in in vivo experimental models. Therefore, HGF is a promising therapeutic agent for the treatment of fatal liver diseases, including fulminant hepatic failure. After performing a number of preclinical tests, our group began an investigator-initiated registered phase I/II clinical trial of patients with fulminant hepatic failure to examine the safety and clinical efficacy of recombinant human HGF. In this article, we will discuss the basic research results as well as the translational research that underpins current attempts to use HGF in various clinical settings.     

Hepatocyte growth factor (HGF) and its therapeutic applications

Hepatocyte growth factor (HGF) also known as "scatter factor" (SF), was identified for the first time as a potent mitogen of primary cultured hepatocytes; it has multiple biological responses in a variety of cells including mitogenic, motogenic, morphogenic and antiapoptotic activities. It is secreted as an inactive single chain protein and isproteolitically cleaved to form an active two chain HGF. The hepatocyte growth factor activator (HGFA) is the principal activator of HGF. HGF exerts its biological effects through transmembrane tyrosine kinase receptor (c-Met). HGF is a growth factor displaying a remarkable ability to promote tissue repair and organ regeneration after injury. Therefore attention should be set on the clinical potential of HGF as a treatment for various diseases.     

HGF and postnatal testis development

Hepatocyte growth factor regulates many cellular functions acting through c-met, its specific receptor with tyrosine kinase activity. We have previously reported that in prepubertal rats HGF is secreted in the seminiferous tubules by purified peritubular myoid cells whereas Sertoli cells do not express HGF mRNA. In the present paper we report that HGF is expressed by the myoid cells during the entire postnatal testicular development studied and secreted in the culture medium. On the contrary, in Sertoli cells HGF starts to be clearly detectable by northern blot at 25 days of age. HGF is expressed and secreted by Sertoli cells isolated from 35-day-old rats and is able to increase the levels of c-met expression of the Sertoli cells. Although the role of HGF during the development of the postnatal testis need further research to be clarified, the data here presented indicate that HGF is one of the growth factors regulating mammalian testicular function.     

Mucosal repair and growth factors: recombinant human hepatocyte growth factor as an innovative therapy for inflammatory bowel disease

The repair of intestinal mucosal injuries is a tightly regulated process involving epithelial restitution, cell proliferation and maturation, and the dedifferentiation of epithelial cells. Deeper injuries also require additional repair mechanisms, including inflammatory processes, angiogenesis, and extracellular-matrix deposition. Once intestinal mucosal injury occurs, numerous growth factors and cytokines, including hepatocyte growth factor (HGF), keratinocyte growth factor, endothelial growth factor, epidermal growth factor, transforming growth factor-β1, intestinal trefoil factor, interleukin (IL)-1, and IL-2, are induced in both the intestinal lumen and submucosa, and these factors cooperatively stimulate epithelial mucosal repair. HGF, a major agent promoting hepatocyte proliferation, also modulates intestinal epithelial cell proliferation and migration, leading to the acceleration of intestinal mucosal repair. Additionally, the proteolytic activation of HGF, which is mediated by HGF activator, is essential for the regeneration of injured intestinal mucosa. Recently, several studies have shown that the administration of recombinant human HGF or HGF gene therapy abrogates disease severity in several animal models of inflammatory bowel disease (IBD). Recombinant human HGF will soon be available for administration to patients with fulminant hepatic failure. Although additional preclinical biological studies are required, HGF has the potential to be an important new treatment modality promoting intestinal mucosal repair in patients with IBD.     

Hepatocyte growth factor inhibits growth of hepatocellular carcinoma cells.

Hepatocyte growth factor (HGF) is a potent mitogen for primary hepatocytes. Therefore, we examined HGF as a possible autocrine growth factor in hepatocellular carcinoma (HCC). We introduced an albumin-HGF expression vector into Fao HCC cells and transgenic mice. Expression of the albumin-HGF vector in Fao HCC cells inhibited their growth in vitro. In vivo, FaoHGF cells produced tumors that averaged 10% of the sizes of G418-resistant controls when transplanted into nude mice. In contrast, hepatocytes from transgenic mice expressing HGF grew more rapidly than did those from normal siblings. Further, growth of eight additional HCC cell lines was inhibited by the addition of recombinant HGF. Finally, of 35 tumor cell lines surveyed, only 6 cell lines expressed HGF mRNA, and no HCC cell line expressed HGF. Although HGF stimulates normal hepatocytes, it is a negative growth regulator for HCC cells.     

Induction of hepatocyte growth factor in stromal cells by tumor-derived basic fibroblast growth factor enhances growth and invasion of endometrial cancer

Tumor progression is often regulated through interactions between carcinoma cells and host stromal cells. In this study of endometrial cancer, we investigated one mechanism potentially involved in hepatocyte growth factor (HGF)-mediated cancer-stromal interactions. Endometrial cancer cells (HEC-1 and ISHIKAWA) expressed the c-met receptor, but HGF did not. HGF, however, did stimulate the proliferation and invasion of these cells. The HGF gene was expressed in stromal cells, which had been separated from primary cultures of endometrial cancers, 6.4 times more than in isolated normal endometrial stromal cells. Immunohistochemical staining revealed immunoreactive HGF in cancer stromal cells, the staining intensity being more pronounced in cancer tissue than in normal endometrium. The conditioned medium from normal epithelial cells and cancer cell lines induced HGF production in normal stromal cells. We identified basic fibroblast growth factor as an HGF inducer derived from endometrial cancer cell lines. Basic fibroblast growth factor derived from tumor cells may induce HGF in endometrial stromal cells, whereas stromal cell-derived HGF leads to the invasive growth of carcinoma cells. These interactions, mediated by HGF and HGF inducers, may play a significant role in the progression of endometrial cancer.     

Hepatocyte growth factor stimulates cell growth and enhances the expression of transforming growth factor α mRNA in AsPC-1 human pancreatic cancer cells

We investigated the effects of hepatocyte growth factor (HGF) and transforming growth factor α (TGF α) on cell growth in four human pancreatic cancer cell lines. Changes in the expression of mRNAs of HGF, c-met, TGF α, and epidermal growth factor receptor (EGFR) by treatment with HGF and TGF α were observed. Cell growth with growth factors was assessed with the MTT assay and compared with basal growth without growth factors. Although HGF stimulated cell growth in AsPC-1, COLO-357, and T3M4 cells, Panc-1 cells showed no response to HGF. TGF α stimulated the growth of all the above cells. The expression of c-met mRNA under nonstimulated conditions was detected with Northern blotting in all cells. Treatment with HGF slightly enhanced the expression of c-met mRNA only in COLO-357 cells. The intensity of EGFR expression was consistent, and HGF mRNA was not detected during induction experiments in any cell type. Concomitant treatment with HGF and TGF α exerted an effect that was additive or less on the growth of all cells. Expression of TGF α was enhanced by HGF treatment only in AsPC-1 cells. These results suggested that HGF and TGF α stimulated cell growth through a final common pathway of signal transduction. Received: November 11, 1998 / Accepted: December 18, 1998