大鼠心肌虚血再灌流后肝细胞再生因子的表达变化

肝细胞再生因子（hepatocyte growth factor, HGF）对多种细胞都具有促进增殖及运动、抗凋亡的作用,对组织器官的发育形成也起到重要作用．在肝脏、肾脏、肺、心脏等器官受损之后的修复过程中,有积极的促进再生的作用．本研究采用了心虚血再灌流大鼠模型,发现心肌细胞受损伤后 6 h 血清中HGF水平显著增高．在比较了肾脏、肺、肝脏、脾脏等组织提取液中HGF的含量之后,发现心虚血再灌流手术后,肾脏、肺、肝脏中HGF的含量变化不明显,而脾脏的提取液中HGF的含量增加显著．对脾脏组织的连续切片进行HGF与血管内皮细胞的特异性标志物von Willanbrand Factor (vWF)免疫组织化学染色研究,发现手术后脾脏中产生HGF的细胞主要为血管内皮细胞．此项研究首次阐明组织器官受损后,远端组织器官的血管内皮细胞能够增加HGF的合成和分泌,增加的HGF通过体液循环到达受损组织器官,促进其修复再生．     

肝细胞生长因子在损伤肾组织中的作用

肝细胞生长因子（hepatocyte growth factor．HGF）是一种多效性生长因子,主要由间质细胞产生,通过自分泌和旁分泌方式作用于上皮细胞、内皮细胞以及间质细胞本身,具有促有丝分裂、促细胞形态形成和调节细胞活动的功能,从而对损伤的器官和组织进行修复。许多新的研究显示,在急性肾损伤时给予外源性HGF可以保护肾小管上皮细胞、重建肾小管结构和维持肾功能完整性。此外,HGF还能有效地抑制与慢性肾脏疾病及慢性肾功能衰竭密切相关的肾间质纤维化的进展过程。     

肝细胞生长因子促进非肝组织再生

肝细胞生长因子除能刺激肝细胞分裂增殖外,还可作用于其它多种细胞,在组织器官的损伤修复中发挥重要作用。     

肝细胞生长因子是一个强的肾营养因子

肝细胞生长因子是目前已知生物活性最广泛的生长因子之一,能刺激多种上皮和内皮细胞进行有丝分裂、运动以及促进肾小管形态发生,在组织器官损伤修复、形态发生和肿瘤转移过程中发挥重要作用,在肾脏的发育、急性损伤、再生中具有较强的作用。     

肝细胞生长因子基因修饰的间充质干细胞治疗肝损伤的研究进展

减轻肝脏损伤、促进肝脏修复和再生始终是肝脏疾病研究中的重点。间充质干细胞(MSCs)是众多具有组织修复和再生能力细胞中的明星细胞,合成的多种细胞因子经旁分泌途径发挥调控细胞生存,调节炎症反应,促进血管再生和减轻纤维化等多种生物学效应,肝细胞生长因子(HGF)便是重点细胞因子之一。基于HGF的信号调控作用,再结合MSCs的干细胞优势,HGF基因修饰间充质干细胞(HGF-MSCs)作为一种干细胞治疗新策略能够发挥“1+1>2”的效果。本文就HGF-MSCs在减轻和修复肝损伤中的研究进展作综述。     

肝细胞生长因子研究进展

肝细胞生长因子是一个多效应生长因子,参与机体多种器官组织细胞的生长。再生和重塑过程。本综述近年来对HGF在生物学方面的研究。包括HGF/c-met受体的生化。结构,基因表达和信号分子转导等方面。     

骨髓间充质干细胞对大鼠急性肾损伤的修复作用

目的：观察外源性骨髓间充质干细胞（Mesenchymal stem cells,MSCs）对庆大霉素（Gentamycin,GM）诱导的大鼠急性肾损伤是否具有治疗作用,并初探其机制。方法：建立腹腔注射庆大霉素致大鼠急性肾损伤模型。实验分为舡常对照组、模型组、MSCs治疗组（模型＋MSCs）、生理盐水组（模型＋生理盐水）。于不同处理后4d分别检测血尿素氮（BUN）和肌酐（Scr）水平,观察肾组织病理改变,免疫印迹及RT-PCR法检测肾组织肝细胞生长因子（Hepatocyte growth factor,HGF）水平。结果：模型组大鼠的BUN及Scr较正常对照组显著升高,且肾小管组织病理损伤严重;而MSCs治疗组大鼠的BUN及Scr水平较生理盐水组显著降低,肾小管组织病理损伤明显减轻。此外。促肾小管损伤修复的肝细胞生长因子（HGF）表达在MSCs治疗组显著高于生理盐水组。结论：MSCs输注可促进庆大霉素所致急性肾小管损伤的修复,改善肾功能,其作用机制可能是与上调肾组织中肝细胞细胞生长因子的表达有关。     

骨髓间充质干细胞对大鼠急性肾损伤的修复作用

目的:观察外源性骨髓间充质干细胞(Mesenchymal stem cells,MSCs)对庆大霉素(Gentamycin,GM)诱导的大鼠急性肾损伤是否具有治疗作用,并初探其机制。方法:建立腹腔注射庆大霉素致大鼠急性肾损伤模型实验分为正常对照组、模型组、MSCs治疗组(模型+MSCs)、生理盐水组(模型+生理盐水)。于不同处理后4d分别检测血尿素氮(BUN)和肌酐(Scr)水平,观察肾组织病理改变,免疫印迹及RT-PCR法检测肾组织肝细胞生长因子(Hepatocyte growth factor,HGF)水平。结果:模型组大鼠的BUN及Scr较正常对照组显著升高,且肾小管组织病理损伤严重;而MSCs治疗组大鼠的BUN及Scr水平较生理盐水组显著降低,肾小管组织病理损伤明显减轻。此外,促肾小管损伤修复的肝细胞生长因子(HGF)表达在MSCs治疗组显著高于生理盐水组。结论:MSCs输注可促进庆大霉素所致急性肾小管损伤的修复,改善肾功能,其作用机制可能是与上调肾组织中肝细胞细胞生长因子的表达有关。     

肝细胞生长因子在骨骼肌再生中的作用研究进展

骨骼肌损伤后的修复包括炎症反应期、修复期、组织重塑期三个阶段。而骨骼肌卫星细胞的激活、增殖与分化和骨骼肌伤后的修复有着密切的关系。骨骼肌损伤后,肝细胞生长因子(HGF)可以自分泌、旁分泌或内分泌的形式,调控肌卫星细胞功能,从而影响损伤骨骼肌的再生。其机制研究表明,HGF可能通过与其受体c-met结合,启动相关信号途径,参与骨骼肌卫星细胞激活、增殖、分化和迁移,从而影响骨骼肌再生进程。     

角质细胞生长因子研究进展

角质细胞生长因子(KGF)从属于成纤维细胞生长因子家族。KGF基因表达受多种细胞因子调控。KGF与受体KGFR特异性的结合发挥其多种生物学功能：参与组织、器官的发育;参与皮肤、胃、肠、肾、膀胱、肺等上皮的损伤修复;减少放、化疗所带来的副作用,具有损伤防护功能;KGF与肿瘤密不可分。     

Hepatocyte growth factor stimulates neutrophil degranulation but not respiratory burst

Neutrophil function is regulated in part by cytokines with growth factor activities for different cell types. Hepatocyte growth factor (HGF) is a cytokine produced during injury to the liver and other organs. Neutrophils are numerous in such tissue injury sites and may be influenced by HGF. In the present study the effect of HGF on neutrophils was investigated. The data show that HGF at 1-10 ng/ml increased lysosomal enzyme release from both specific and azurophilic granules of cytochalasin-B treated neutrophils. The release of specific granule contents in response to N-formyl-methionyl-leucylphenylalanine was also increased by HGF. In contrast there were no significant effects of HGF on neutrophil respiratory burst, adherence or locomotion. It is concluded that HGF modulates neutrophil granule exocytosis.     

Differential expression of hepatocyte growth factor in liver, kidney, lung, and spleen following burn in rats

Hepatocyte growth factor (HGF) plays a role as an organotropic factor for regeneration of injured organs. HGF is synthesized as an inactive single-chain precursor which is then converted to a biologically active heterodimeric form by proteolytic processing. Burn is the insult that results in hypovolemia which causes systemic organ injury. In this study, we investigated the induction and activation of HGF in various rat organs following burn trauma. Tissue HGF content determined as the total amount of the single-chain and heterodimeric form increased significantly in liver, lung, spleen, and kidney 12 h after burn. Molecular analysis revealed that HGF in these four organs of control rats was the single-chain precursor. In the burned rats, HGF was the single-chain form in the liver and lung, whereas heterodimeric HGF was detected in the spleen and kidney. Tissue protein content, an index of tissue injury, decreased significantly in the spleen and kidney, indicating that tissue damage was severe in these two organs. These results suggest that burn induces the production of HGF in various organs, and that the induced HGF is activated according to the severity of tissue damage caused by burn.     

Skeletal muscle injury induces hepatocyte growth factor expression in spleen

Hepatocyte growth factor (HGF) is present in skeletal muscle and facilitates skeletal muscle regeneration by activating quiescent satellite cells and stimulating their proliferation. However, possible involvement of HGF from non-muscle organs during muscle regeneration is still uncovered. Since liver injury induces HGF expression in distal HGF-producing organs such as lung, kidney and spleen, we examined if this is the case in muscle injury in analogy. In rat femoral muscle, HGF protein levels were elevated within 1 h after muscle injury, with a simultaneous proteolytic activation of HGF protein. Semiquantitative RT-PCR analysis revealed an elevation of HGF mRNA expression after muscle injury in the liver and spleen, and also an increase of HGF protein levels in the spleen, suggesting the presence of endocrine HGF-inducing factor(s) during muscle regeneration. Indeed, the sera from the rat with muscle regeneration were capable of inducing HGF mRNA expression when applied to primary cultured spleen cells from intact rats. These results indicated that skeletal muscle injury induces HGF expression in the non-muscle HGF-producing organs, especially in the spleen, and suggested the possible involvement of non-muscle organ-derived HGF in activation/proliferation of satellite cells during muscle regeneration.     

The emerging role of hepatocyte growth factor in renal diseases

Hepatocyte growth factor (HGF), a kringle-containing polypeptide, acts on various epithelial cells to regulate cell growth, cell motility, and morphogenesis. HGF also accelerates tissue regeneration of injured organs and is regarded as a key molecule in organ regeneration. Besides the regeneration of the liver, HGF also plays a role in the renal regeneration. In addition, an adaptive alteration of HGF status in various renal diseases occurs. However, the precise role of HGF in various renal diseases remains elusive. The signaling pathways of HGF may be associated with renal diseases. In this review, we will try to provide an in-depth understanding of the underlying role of HGF and its possible interactions with other molecules in renal diseases.     

Lung may have an endocrine function producing hepatocyte growth factor in response to injury of distal organs.

Hepatocyte growth factor (HGF) is a potent growth factor for various epithelial cells including mature hepatocytes and renal tubular cells. When 70% of the rat liver was excised, HGF mRNA in the intact lung markedly increased at 6 h later, then decrease to normal levels at 24 h. A similar marked increase of HGF mRNA was found in the lung of rats with hepatitis induced by CCl4. Moreover HGF mRNA in the intact lung also increased to about a 5 times higher level than the normal, within 12 h after unilateral nephrectomy. Isolated alveolar macrophages significantly expressed HGF mRNA, yet the amount remained unchanged after injury of the liver. The marked increase of HGF mRNA in lungs of partially hepatectomized rats remained even after removal of alveolar macrophages. In situ hybridization showed a marked increase of HGF mRNA signal found in endothelial cells in the lung after partial hepatectomy. We postulate that endothelial cells in the lung recognize damage of distal organs through a mediator and that lung-derived HGF may contribute to tissue repair or regeneration of injured organs, through endocrine-related mechanisms.     

Marked induction of hepatocyte growth factor mRNA in intact kidney and spleen in response to injury of distant organs.

Hepatocyte growth factor (HGF) is a potent mitogen for various epithelial cells, including mature hepatocytes and renal tubular cells. Here, HGF mRNA was found to be markedly increased in non-injured kidney and spleen, when the liver or kidney in rats was injured by 70% partial hepatectomy or unilateral nephrectomy. HGF mRNA increased to 3-4 fold higher level than the normal in the kidney and spleen as well as in the remnant liver after partial hepatectomy. Similarly, HGF mRNA markedly increased in the spleen as well as in the remnant kidney after unilateral nephrectomy. These results suggest that the onset of injury to the liver or kidney may be recognized by distal non-injured organs by the signalling of a humoral factor and that HGF derived from these organs may be involved in the regeneration of liver or kidney, through an endocrine mechanism.     

Tissue distribution of hepatocyte growth factor receptor and its exclusive down-regulation in a regenerating organ after injury.

Using 125I-labeled hepatocyte growth factor (HGF) as a ligand, we examined the tissue distribution of the HGF receptor in adult rats. Specific binding of 125I-HGF was detected in the plasma membranes of liver, spleen, kidney, lung, adrenal gland, pituitary, and thyroid. Scatchard analysis of HGF binding in liver, spleen, kidney, lung, and adrenal gland revealed the presence of a single class of high affinity receptor with a dissociation constant (Kd) of 20-30 pM. The maximum number of binding sites (Bmax) was determined to be 400-3,000 sites per ng of plasma membrane protein, the highest number being in the liver. Such a wide distribution of a high affinity HGF receptor indicates that HGF may be a multifunctional growth factor, targeting to a variety of organs, and not restricted to liver. After 70% partial hepatectomy, specific binding of 125I-HGF to membranes of the residual liver rapidly decreased, but there was no change in the kidney, lung, and spleen. On the other hand, after unilateral nephrectomy rapid down-regulation of the HGF receptor was clearly evident in the remaining kidney, but not in other organs including the liver. These findings suggest the presence of control mechanisms governing HGF receptor function only in a regenerating organ after injury.     

Arginine-specific gingipains from Porphyromonas gingivalis stimulate production of hepatocyte growth factor (scatter factor) through protease-activated receptors in human gingival fibroblasts in culture

Cystein proteinases (gingipains) from Porphyromonas gingivalis cleave a broad range of in-host proteins and are considered to be key virulence factors in the onset and development of adult periodontitis and host defense evasion. In periodontitis, an inflammatory disease triggered by bacterial infection, the production of hepatocyte growth factor (HGF) is induced not only by various factors derived from the host, such as inflammatory cytokines, but also by bacterial components. In this study we examined the possible enhanced production of HGF produced by human gingival fibroblasts upon stimulation with gingipains. Arginine-specific gingipain (Rgp) caused a marked production of HGF into the supernatant, the induction of HGF expression on the cell surface, and the up-regulation of HGF mRNA expression in a dose-dependent and an enzymatic activity-dependent manner. Because it has been reported that Rgp activated protease-activated receptors (PARs), we examined whether the induction of HGF triggered by Rgps on human gingival fibroblasts occurred through PARs. An RNA interference assay targeted to PAR-1 and PAR-2 mRNA revealed that gingipains-induced secretion of HGF was significantly inhibited by RNA interference targeted to PAR-1 and PAR-2. In addition, the Rgps-mediated HGF induction was completely inhibited by the inhibition of phospholipase C and was clearly inhibited by RNA interference targeted to p65, which is an NF-kappaB component. These results suggest that Rgps activated human gingival fibroblasts to secrete HGF in the inflamed sites and the mechanism(s) involved may actively participate in both inflammatory and reparative processes in periodontal diseases.     

INDUCTION OF HEPATOCYTE GROWTH FACTOR IN THE LIVER, KIDNEY AND LUNG FOLLOWING TOTAL BODY IRRADIATION IN RAT

Hepatocyte factor (HGF) has been shown to have a pleiotropic function to act as a potent organotropic factor in the regeneration of injury in various organs, including the liver, kidney and lung. To examine the involvement of HGF in radiation injury, the authors analysed the changes in HGF mRNA and HGF protein levels in the rat organs (liver, lung, kidney) and plasma following 6 Gy of total body irradiation. Expression of HGF mRNA in the liver and kidney increased 6–48 h after total body irradiation and returned to previous values 1 week later. HGF protein levels in lung and liver showed 1.3-2 fold elevations 1–2 weeks after irradiation (P< 0.05). HGF levels in plasma stayed at undetectable levels up to 1 month after total body irradiation. The labelling index determined 2 weeks and 1 month after total body irradiation indicated no enhancement of regeneration. Thus, total body irradiation induced transient HGF elevation in these organs without enhancement of regeneration