Serum hepatocyte growth factor and clinical outcome in biliary atresia

Purpose

Biliary atresia (BA) remains one of the most intractable liver diseases leading to liver fibrosis. Serum hepatocyte growth factor (HGF) has been shown to increase in cirrhotic patients. The aim of this study was to investigate the possible role of HGF in BA.

Methods

Serum levels of HGF were determined using an enzyme-linked immunosorbent assay from 28 BA patients and 25 healthy children. The patients were categorized into 3 groups according to their clinical outcomes (good, fair, and poor): group A (good), jaundice-free patients (total bilirubin [TB] < 2.0 mg%); group B (fair), patients with mild to moderate jaundice (TB, 2 to 10 mg%); and group C (poor), patients with marked jaundice (TB > 10 mg%). Unpaired t test and analysis of variance (ANOVA) with post-hoc tests were used. Data were expressed as mean and SEM.

Results

Serum HGF levels in BA patients were higher than the controls (P = .02). Subgroup analysis found that there were 12 patients in group A, 8 patients in group B, and 8 patients in group C. The mean age of patients in groups A, B, and C were 5.34 ± 0.52, 7.45 ± 1.98, and 5.49 ± 1.57 years (P > .05). Serum HGF in controls and groups A, B, and C were 0.24 ± 0.03, 0.28 ± 0.04, 0.36 ± 0.09, and 0.56 ± 0.07 ng/mL, respectively. Serum HGF levels in BA patients with poor outcome were higher than patients with good outcome (P = .02). There was no difference in serum HGF of BA patients with fair outcome compared with other groups.

Conclusions

Serum HGF is elevated in BA. Furthermore, BA patients with poor outcome have significantly elevated HGF compared with patients with good outcome. Serum HGF levels may be predictive of prognosis with respect to the progression of liver dysfunction. However, the results of HGF in patients with fair outcome are inconclusive, probably because of the small sample size. Further studies are needed to elucidate the detailed mechanisms.     

Plasma hepatocyte growth factor levels are increased in systemic inflammatory response syndrome

Interleukin-1 (IL-1), a cytokine released from macrophages by endotoxin stimulation, has been shown to upregulate the genetic expression of the hepatocyte growth factor (HGF). The present study was conducted to determine whether plasma HGF is increased in patients with systemic inflammatory response syndrome (SIRS). The plasma levels of HGF, endotoxin, and beta-glucan were measured in 41 surgical patients without hepatic diseases, 18 of whom had been diagnosed with sepsis, and 33, with nonseptic SIRS. The plasma HGF was found to be significantly increased in the 18 patients with sepsis, at 0.69±0.47 ng/ml (mean ± SD), and in the 23 patients with nonseptic SIRS, at 0.49±0.37 ng/ml, compared to values in 40 normal controls, at 0.10±0.03 ng/ml (P<0.001). No significant correlations were observed between the plasma levels of HGF and endotoxin (r=0.02) or beta-glucan (r=–0.05) in any of the patients; however, plasma HGF was significantly correlated with the WBC count (r=0.34, P<0.05) and with total bilirubin (r=0.45, P<0.01). Plasma HGF was also strongly correlated with alanine transaminase (ALT) in 8 patients with ALT levels higher than 50 U/I (r=0.70), but there was no such correlation in 33 patients with ALT levels of 50 U/I or less (r=0.30). Thus, although the clinicopathologic significance of HGF is not well understood, the present findings indicate that plasma HGF increases in response to infection or inflammation.     

Direct transfer of hepatocyte growth factor gene into kidney suppresses cyclosporin A nephrotoxicity in rats.

BACKGROUND: The clinical utility of cyclosporin A (CsA) has been limited by its nephrotoxicity, which is characterized by tubular atrophy, interstitial fibrosis and progressive renal impairment. Hepatocyte growth factor (HGF), which plays diverse roles in the regeneration of the kidney following acute renal failure, has been reported to protect against and salvage renal injury by acting as a renotropic and anti-fibrotic factor. Here, we investigated protective effects of HGF gene therapy on CsA-induced nephrotoxicity by using an electroporation-mediated gene transfer method. METHODS: CsA was orally administered as a daily dose of 30 mg/kg in male Sprague-Dawley rats receiving a low sodium diet (0.03% sodium). Plasmid vector encoding HGF (200 micro g) was transferred into the kidney by electroporation. RESULTS: HGF gene transfer resulted in significant increases in plasma HGF levels. Morphological assessment revealed that HGF gene transfer reduced CsA-induced initial tubular injury and inhibited interstitial infiltration of ED-1-positive macrophages. In addition, northern blot analysis demonstrated that cortical mRNA levels of TGF-beta and type I collagen were suppressed in the HGF group. Finally, HGF gene transfer significantly reduced striped interstitial phenotypic alterations and fibrosis in CsA-treated rats, as assessed by alpha-smooth muscle actin expression and Masson's trichrome staining. CONCLUSIONS: These results suggest that HGF may prevent CsA-induced tubulointerstitial fibrosis, indicating that HGF gene transfer may provide a potential strategy for preventing renal fibrosis.     

断流术对肝硬化患者术后肝纤维化的影响

目的 探讨脾切除贲周血管离断术对乙肝肝硬化门静脉高压症患者无创性肝纤维化指标及肝功能的影响.方法 20例未经抗病毒治疗的乙肝肝硬化门脉高压患者,Child-PughA级12例,B级8例,分别于断流术前后,采用ELISA法测定血清PDGF、CTGF;电化学发光法测定透明质酸（HA）、三型前胶原（PcⅢ）、层黏连蛋白（LN）、四型胶原（cⅣ）;采用全自动生化分析仪及血细胞计数仪测定总胆红素（TBIL）、转氨酶（AST、ALT）、胆碱酯酶（CHE）、前白蛋白（PA）、WBC及PLT.结果 ①血清PDGF、CTGF及肝纤四项指标较术前明显下降.②总胆红素（TBIL）较术前明显降低;前白蛋白（PA）、胆碱酯酶（CHE）较术前有所升高,差异明显.③白细胞、血小板较术前升高差异有统计学意义.结论 断流术不仅能够减少肝硬化门静脉高压的多种并发症,同时在改善肝功能、凝血功能及延缓肝纤维化的发展上起了重要作用.     

Laser-induced thermotherapy (LITT) elevates mRNA expression of connective tissue growth factor (CTGF) associated with reduced tumor growth of liver metastases compared to hepatic resection

BACKGROUND AND OBJECTIVES: Proliferation and synthesis of hepatocellular tissue after tissue damage are promoted by specific growth factors such as hepatic tissue growth factor (HGF) and connective growth factor (CTGF). Laser-induced thermotherapy (LITT) for the treatment of liver metastases is deemed to be a parenchyma-saving procedure compared to hepatic resection. The aim of this study was to compare the impact of LITT and hepatic resection on intrahepatic residual tumor tissue and expression levels of mRNA HGF/CTGF within liver and tumor tissue. STUDY DESIGN/MATERIALS AND METHODS: Two independent adenocarcinomas (CC531) were implanted into 75 WAG rats, one in the right (untreated tumor) and one in the left liver lobe (treated tumor). The left lobe tumor was treated either by LITT or partial hepatectomy. The control tumor was submitted to in-situ hybridization of HGF and CTGF 24-96 hours and 14 days after intervention. RESULTS: Volumes of the untreated tumors prior to intervention were 38+/-8 mm(3) in group I (laser), 39 +/- 7 mm(3) in group II (resection), and 42 +/- 12 mm(3) in group III (control) and did not differ significantly (P > 0.05). Fourteen days after the intervention the mean tumor+/-SEM volume of untreated tumor in group I (laser) [223 +/- 36] was smaller than in group II (resection) [1233.28 +/- 181.52; P < 0.001], and in group III (control) [978.92 +/- 87.57; P < 0.003]. Forty-eight hours after the intervention intrahepatic mRNA expression level of HGF in group II (resection) was almost twofold higher than in group I (laser) [7.2 +/- 1.0 c/mf vs. 3.9 +/- 0.4 c/mf; P<0.01]. Fourteen days after the intervention intrahepatic mRNA expression level of CTGF in group I (laser) was higher than in group II (resection) [13.89 +/- 0.77 c/mf vs. 9.09 +/- 0.78 c/mf; P < 0.003]. CONCLUSIONS: LITT leads to a decrease of residual tumor growth in comparison to hepatic resection. Accelerated tumor growth after hepatic resection is associated with higher mRNA level of HGF and reduced tumor growth after LITT with higher mRNA level of CTGF. The increased CTGF-mediated regulation of ECM may cause reduced residual tumor growth after LITT.     

Serum hepatocyte growth factor concentration in patients with various degrees of chronic renal failure

Summary: Serum hepatocyte growth factor (HGF) concentrations were measured in healthy volunteers, chronic renal failure patients without renal replacement therapy and haemodialysis patients. Serum HGF concentrations in healthy volunteers, chronic renal failure patients and haemodialysis patients were 0.18 ± 0.04 (s.d.), 0.28 ± 0.06 and 0.46 ± 0.22 ng/mL, respectively. Serum HGF concentration in chronic renal failure patients was significantly higher than that in healthy volunteers. Serum HGF concentration in haemodialysis patients was significantly higher than those in healthy volunteers and chronic renal failure patients. There was no regression of serum HGF concentration on age, sex, history of haemodialysis, prehaemodialysis serum creatinine concentration, and serum tumour necrosis factor (TNF)-α concentration. We conclude that chronic renal disease and haemodialysis therapy are contributing factors to an increased serum HGF concentration.     

急性肝衰竭大鼠载肝细胞生长因子纳米粒子肝细胞移植后有丝分裂指数和Ki-67表达变化及意义

目的 探讨急性肝衰竭(ALF)大鼠载肝细胞生长因子(HGF)的聚乳酸-氧-羧甲基壳聚糖(PLA-O-CMC)纳米粒子肝细胞移植后有丝分裂指数和Ki-67抗原的表达变化及意义.方法 D-氨基半乳糖腹腔内注射制作大鼠ALF模型,48 h后分别将Ⅰ型胶原(Ⅰ组)、PLA-O-CMC纳米粒子(Ⅱ、Ⅳ组)、载HGF的PLA-O-CMC纳米粒子(Ⅲ组)培养的大鼠肝细胞(均为5×107个,5 ml)移植到ALF大鼠腹腔内.以每日静脉注射HGF 10μg/kg×7 d(Ⅳ组)、5 Ml RPMI 1640腹腔内注射(Ⅴ组)作为对照.观察其14 d存活率、血清及肝组织HGF浓度、肝组织病理及有丝分裂指数(MI)、Ki-67变化.结果移植后14 d Ⅰ～Ⅴ组ALF大鼠的存活率分别为50.00％、68.75％、81.25％、75.00％、18.75％.各纳米移植组高于V组.Ⅲ组3 d时肝组织HGF浓度最高,平均为5882.91 μG／L.Ⅲ组肝组织结构恢复更快,5 d时平均MI 10.20％0、7 d时平均MI 10.20‰、7 d时Ki-67平均标记指数16.8‰,均高于Ⅴ组.结论 应用载HGF的PLA-O-CMC纳米粒子培养的大鼠肝细胞腹腔内移植治疗ALF大鼠能促进肝再生相关抗原表达.

Abstract：

Objective To evaluate the change and significance of Ki-67 antigen expression follow ing hepatocyte transplantation using hepatocyte growth factor (HGF) loaded polylactic acid-O-carboxymethylchitosan (PLA-O-CMC) nanoparticles in rats with acute liver failure (ALF). Methods ALF models of rats were established by D-galactosamine intraperitoneal injection. Rat hepatocytes type Ⅰ collagen suspension (group Ⅰ ),rat hepatocytes co-cultured with PLA-O-CMC nanoparticles ( groups Ⅱ ,Ⅳ ) and rat hepatocytes co-cultured with HGF loaded PLA-O-CMC nanoparticles ( group Ⅱ ) (5 × 107 cells each group,5 ml) were transplanted into the abdominal cavity of SD rats at 48 h after D-Gal injection. Intravenous injection of HGF ( 10 μg/kg for 7 days) ( group Ⅳ ) and RPMI 1640 injection (group Ⅴ ) were used as the negative groups. The 14th-day survival rate of rats,pathological change and mitotic index of liver,Ki-67 antigen labeling index of ALF rat livers were observed. Results The 14th-day survival rate in groups Ⅰ -Ⅴ was 50.00％,68. 75％,81.25％,75.00％,18.75％,and that in nano-transplanted groups was higher than in group Ⅴ. At the 3rd day,the concentration of HGF in liver tissue of group Ⅲ,average 5882. 91 μg/L was the highest. The hepatic lobules structure in group Ⅲ recovered faster. The average mitotic index in group Ⅱ at the 5th day was 10. 20‰ and the average Ki-67 labeling index at the 7th day was 16. 8‰,which were all higher than in group Ⅴ. Conclusion Intraperitoneal transplantation of HGF loaded PLA-O-CMC nanoparticle-attached hepatocytes for treatment of ALF can promote the liver regenerationassociated antigen expression.     

The role of hepatocyte growth factor in growth plate cartilage

To investigate the physiological role of hepatocyte growth factor (HGF) in endochondral bone formation, we examined the expression of HGF and its receptor c-met and the effects of HGF on growth plate chondrocytes. HGF was highly expressed in the prehypertrophic zone and hypertrophic zone in rat costal growth plate cartilage. The expression of HGF increased in rabbit chondrocytes as they matured in culture. Conversely, c-met expression was down regulated along maturation of growth plate chondrocytes. HGF had weak stimulatory effects on DNA and proteoglycan synthesis of growth plate chondrocytes. However, HGF strongly inhibited expression of terminal differentiation-related phenotypes, such as type X collagen and alkaline phosphatase (APase) synthesis and cartilage matrix mineralization. When HGF was removed from the cultures, cells quickly expressed type X collagen and APase. Once chondrocytes differentiated to mature chondrocytes, HGF did not inhibit further differentiation of these cells. These results suggested that HGF is a negative regulator of terminal differentiation of growth plate chondrocytes.. Received: Feb. 12, 1998 / Accepted: March 12, 1998     

Transgene-derived hepatocyte growth factor attenuates reactive renal fibrosis in aristolochic acid nephrotoxicity.

BACKGROUND: Hepatocyte growth factor (HGF) has been demonstrated to attenuate acute tubular necrosis and interstitial fibrosis in a variety of rodent models of kidney disease. We investigated how HGF could affect chronic toxic nephropathy/interstitial fibrosis caused by aristolochic acid (AA). METHODS: Wild-type and HGF transgenic mice received daily intraperitoneal injections of AA for 14 days. At sacrifice, kidneys were removed and used for microscopy examination and in vitro studies. To determine the molecular mechanisms of anti-fibrotic effects of HGF, cultured murine tubular epithelial cells (mProx24) were employed. RESULTS: Significant tubular degeneration was observed in both the transgenic and the wild-type mice to the same degree after 2 weeks treatment with AA. Interstitial fibrosis subsequently developed in the wild-type mice 4 weeks after cessation of AA administration. However, the transgenic mice manifested less fibrotic changes. Decreased expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) and increased matrix metalloproteinase-9 activity could partially account for the attenuation of fibrogenesis in the transgenic mouse kidney. HGF at 10 and 100 ng/ml could block TIMP-1 gene expression in mProx24 induced by epidermal growth factor, but a decrease in the number of mProx24 via apoptosis induced by AA was blocked only by HGF at 100 ng/ml. CONCLUSION: Circulating transgene-derived HGF (2-10 ng/ml) could not prevent tubular degeneration caused by AA, but attenuated interstitial fibrogenesis during tubular regeneration. These findings suggest a possible therapeutic efficacy for renal interstitial fibrosis following tubular degeneration even of low-dose HGF.     

The impairment of hepatocytes and sinusoidal endothelial cells during cold preservation in rat fatty liver induced by alcohol and the beneficial effect of hepatocyte growth factor

A fatty liver resulting from alcohol intake is often unattractive for grafting. In this study, we investigated the impairment of hepatocytes and sinusoidal endothelial cells (SECs) during cold preservation of alcohol-induced fatty liver and examined the efficacy of human recombinant hepatocyte growth factor (hrHGF). Rats were fed an alcohol diet. We performed histological examinations of the hepatocytes and observed the ultrastructural alteration of the SECs. Additionally, we measured hepatic transaminase and peroxidative lipids for hepatocellular injury and the hyaluronic acid uptake rate (HUR) to determine SEC injury. We added hrHGF to University of Wisconsin (UW) solution to assess the protective effect of the agent. Numerous fatty deposits were observed in ethanol-induced fatty livers. These grew with the duration of cold storage. Hepatic transaminases of the effluents increased during cold preservation in the livers of alcohol-treated rats. Additionally, peroxidative lipids in the effluents increased during cold preservation in the livers of alcohol-treated rats, whereas they were undetectable in non-alcohol-treated rat livers. The sinusoidal endothelium had severely deteriorated in the livers of alcohol-treated rats. Further, the HUR decreased with ethanol treatment and/or cold preservation. The addition of hrHGF suppressed the increase of hepatic transaminase in the effluent of cold-preserved alcohol-treated livers. Peroxidative lipids in the same effluents were undetectable. In fatty livers, both hepatocytes and SECs received severe damage during cold preservation. Furthermore, we demonstrated that hepatocellular injury was significantly inhibited by hrHGF.     

重组人肝细胞生长因子在Celisor液中对无心跳供肝的保护作用及其机制

目的 探讨Celsior(CS)液中添加重组人肝细胞生长因子(rhHGF)对无心跳供肝(NHBD)的保护作用及其可能机制.方法 利用大鼠肝移植模型,比较添加rhHGF(10μg/L)的CS液(实验组)与添加等量生理盐水的CS液(对照组)两组门静脉再通后胆汁产生量、肝组织含水量及肝酶水平,观察生存率,TUNEL法检测肝细胞凋亡及常规病理组织学检查.结果 与对照组比较,试验组NHBD供肝移植后在门静脉再通1 h,3 h及6 h胆汁产生量明显增多(P<0.05),ALT与AST水平明显降低(P<0.05);在门静脉再通1 h肝组织含水量及肝细胞凋亡指数明显下降(P<0.05);7 d大鼠生存率明显升高(P<0.05),病理组织学提示肝细胞水肿变性明显减轻,无肝细胞坏死及肝窦淤血.结论 CS灌注保存液中添加外源性rhHGF可明显改善其对NHBD供肝的保存效果,这可能与其减少肝细胞凋亡有关.     

FGFR3在大鼠肝硬化模型中的动态表达研究

目的：观察大鼠肝硬化形成过程中成纤维细胞生长因子受体3（Fibroblast growth factor receptor3,FGFR3）的表达变化。方法：70只雄性SD大鼠,随机取10只作为对照组,其余60只作为肝硬化组。采用剂量频次渐变式四氯化碳（CCL）腹腔内注射建立肝硬化大鼠模型。检测2组大鼠的血清ALT、体重、肝体比,病理组织行包括HE和嗜银染色．并采用荧光定量聚合酶链反应（real—timePCR）和蛋白质印迹（Western blot）检测FGFR3基因和相应蛋白在肝硬化形成过程中的表达变化。结果：肝硬化组大鼠的血清ALT、肝体比和死亡率均显著高于对照组（P均〈0．01）;而体重则显著低于对照组（P〈0．01）;肝硬化组大鼠肝组织大体观察、HE染色及嗜银染色均呈明显肝硬化表现,而对照组则无该表现：real-timePCR及Western-blot结果显示,FGFR3在肝硬化形成过程中总体表达逐渐增强。结论：剂量频次渐变式GEl4腹腔内注射法是一种高效、低成本的大鼠肝硬化建模方法。而肝组织FGFR3在肝硬化发生、发展过程中的动态表达在一定程度上反映了肝纤维化及肝硬化程度。     

肝细胞生长因子对大鼠背部超长任意皮瓣存活率影响的实验研究

目的：探讨肝细胞生长因子对大鼠背部超长任意皮瓣血管生成的作用及皮瓣存活率的影响。方法：建立大鼠背部超长任意皮瓣8.0cm×2.0cm动物模型,直接皮下注射50ng/ml肝细胞生长因子溶液,术后7天观察皮瓣颜色、质地、毛细血管回流、坏死范围、切割皮瓣出血情况;计算皮瓣的存活面积;免疫组化染色后在显微镜下计算毛细血管平均密度。通过自身前后对照、与生理盐水组对照,比较两者的差异。结果：肝细胞生长因子组皮瓣的存活率81.45%±2.74%,与对照组的42.82%±7.03%比较,差别有统计学意义（P〈0.05）;实验前实验组和对照组毛细血管数分别为12.70±1.35、12.31±1.22,两者差别无统计学意义（P〉0.05）;实验后实验组和对照组毛细血管数分别为39.67±4.83、21.50±1.87,两者差别有统计学意义（P〈0.05）;实验组及对照组实验后毛细血管密度高于实验前,差别有统计学意义（P〈0.05）。结论：肝细胞生长因子能促进皮瓣血管内皮细胞的生成,提高皮瓣的存活率。     

Evaluation of liver function by means of serum cytokeratin 18 and hepatocyte growth factor levels in patients with obstructive jaundice

Objective: To evaluate the serum levels of cytokeratin 18 (CK18) and hepatocyte growth factor (HGF) in obstructive jaundice patients before and after treatment and thereby to detect the possible role of CK18 and HGF in patients with obstructive jaundice.

Patients and methods: Forty patients who had obstructive jaundice and 40 healthy control subjects were included in the study. Patients were treated using percutaneous, endoscopic or surgical approaches. Blood samples were obtained at the day before and 7 days after the intervention for obstructive jaundice. Serum HGF and CK18 concentrations were determined by ELISA method.

Results: There were statistically significant decreases in HGF, CK18, total bilirubin and direct bilirubin serum levels, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, and alkaline phosphatase activities and white blood cell count when compared with pre-treatment levels.

Conclusion: Evaluating pre- and post-treatment serum HGF and CK18 levels suggested that there was an apoptosis in obstructive jaundice patients and this apoptosis decreased after the decompression of the biliary tract. We also demonstrated that HGF levels were altered at biliary obstruction compared to healthy controls and the levels of this biomarker also decreased after decompression of biliary obstruction. We concluded that these biomarkers can be used as predictors of liver injury in biliary obstruction.     

载肝细胞生长因子的纳米粒子治疗急性肝衰竭大鼠

目的 观察载肝细胞生长因子(HGF)的聚乳酸-O-羧甲基壳聚糖(PLA-O-CMC)纳米粒子培养的大鼠肝细胞腹腔内移植对急性肝衰竭(ALF)大鼠的治疗效果.方法 分别将5 ml培养24 h的大鼠肝细胞(5.0×107个)(Ⅰ组)、PLA-O-CMC纳米粒子培养的大鼠肝细胞(Ⅱ组)、载HGF的PLA-O-CMC纳米粒子培养的大鼠肝细胞(Ⅲ组)移植到ALF大鼠腹腔内,以PLA-O-CMC纳米粒子培养的大鼠肝细胞腹腔移植加每天静脉注射HGF 10 μg/kg×7 d(Ⅳ组)和5 ml RPMI 1640培养基腹腔内注射(Ⅴ组)作为对照.观察受体大鼠存活率、肝功能、肝组织光镜和电镜变化.结果 移植后14d大鼠的存活率Ⅰ～Ⅴ组分别为50.00％、68.75％、81.25％、75.00％和18.75％,各移植组高于对照组,Ⅲ组最高.移植后24 h,Ⅱ～Ⅳ组各项肝功能指标开始好转,至移植后7d,各组间除谷丙转氨酶(ALT)外,差异无统计学意义(P＞0.05).Ⅲ组的肝功能和肝脏病理损害恢复最快,其次为Ⅳ、Ⅱ、Ⅰ组,Ⅴ组恢复最慢、最差.结论 应用载HGF的PLA-O-CMC纳米粒子培养的大鼠肝细胞腹腔内移植治疗ALF大鼠能逆转肝功能,提高生存率,较静脉途径给予HGF的治疗效果更好.     

Administration of rhHGF-activator via portal vein stimulates the regeneration of cirrhotic liver after partial hepatectomy in rats

BACKGROUND/AIMS: Cirrhotic liver has less ability to regenerate than normal liver, but it can produce the precursor of hepatocyte growth factor (proHGF) similarly to normal liver after resection. Studies were performed to examine whether the exogenous administration of recombinant human (rh) HGF-activator converts proHGF to biologically active (mature) HGF, inducing an enhancement of liver regeneration in cirrhosis. MATERIALS AND METHODS: Rats with liver cirrhosis were treated by 45% partial hepatectomy, and rhHGF-activator or vehicle was injected via the portal vein 24 h after resection. Liver injury and its regeneration, the conversion of proHGF to mature HGF, and the activation of its signal through HGF receptor (c-Met) were analyzed. RESULTS: rhHGF-activator improved the recovery of liver function after resection in cirrhotic liver as compared with the control group. rhHGF-activator also enhanced the proliferating cell nuclear antigen labeling index and liver regeneration rate. rhHGF-activator converted the proHGF to mature HGF, showing the maximal effect at 10 min after injection, which was followed by tyrosine phosphorylation of insulin receptor substrate (IRS)-1, and the association of IRS-1 with c-Met and phosphatidylinositol 3-kinase. CONCLUSIONS: Results demonstrate that the administration of rhHGF-activator stimulates the recovery of liver function and regeneration after resection in cirrhotic liver through the activation of proHGF and its intracellular signal. It may be potentially useful treatment for patients with liver cirrhosis.     

异种肝细胞移植防治大鼠急性肝功能衰竭

目的: 探讨异种肝细胞移植对大鼠急性肝功能衰竭的治疗效果. 方法: 切除大鼠90%肝脏,建立急性肝功能衰竭模型.分离异种豚鼠和同种异体Sprague-Dawley鼠肝细胞,切肝术前1天植入受体脾脏内.观察受试大鼠存活时间、切肝术后24小时血生化改变和脾脏切片表现. 结果: ①中位存活时间,对照组为21小时,同种组为56小时,异种组为40小时.同种组存活时间较对照组长(P<0.01),异种组亦延长(P<0.05).②移植组部分血生化指标有所改善.异种组中仅血糖和凝血酶原时间改善较明显(P<0.05),同种组中谷丙转氨酶、总胆红素、血糖和凝血酶原时间都有明显改善(P<0.05或P<0.01).③肝细胞植入后48小时,异种组脾脏内仅存少量萎缩的肝细胞,同种组脾脏内仍散在健存肝细胞. 结论: 异种肝细胞移植对大鼠急性肝功能衰竭有防治作用;要提高移植效果,首先需克服早期的免疫排斥.     

Changes of clotting factors (7, 9 and 10) and hepatocyte growth factor in patients with thrombotic microangiopathy after bone marrow transplantation

To investigate risk factors for thrombotic microangiopathy (TMA) after bone marrow transplantation (BMT), the levels of three clotting factors (7, 9 and 10) and hepatocyte growth factor (HGF) were measured. Among 46 consecutive patients who underwent BMT, six developed TMA and 40 did not. The levels of the clotting factors and HGF did not differ significantly between the six patients with TMA and the 40 patients without it. In two patients who developed TMA during the earlyperiod after BMT, however, the levels of the three clotting factors were significantly decreased even before BMT, along with a significant increase of HGF. These findings suggest that patients with severe hepatic dysfunction before BMT, especially those with impaired protein synthesis, had an increased risk of developing TMA soon after BMT. It was also suggested that measurement of clotting factors (7, 9 and 10) and HGF may be useful to predict the occurrence of TMA in the early period after BMT.     

肝细胞生长因子在防治大鼠腓肠肌废用性萎缩中的作用

目的观察肝细胞生长因子(HGF)对大鼠后肢(石膏固定4周后)的腓肠肌湿重及收缩功能的影响,探讨其在大鼠废用性骨骼肌萎缩防治中的作用。方法选用雄性Wistar大鼠24只,随机分为空白组(8只)、对照组(8只)和实验组(8只)。空白组不予任何处理,笼中自由活动。按照Jozsa等的方法,将对照组和实验组大鼠右后肢用可塑性石膏由足跖管型固定至膝上1 cm处,膝关节固定于屈曲位100°,踝关节固定于跖屈60°位,共4周。固定当天开始,实验组每人予HGF腓肠肌注射(剂量：10 mg/kg,浓度：10 mg/mL),1次/ d,共注射28 d；对照组每天予等量生理盐水腓肠肌注射。4周后完整解剖右后肢腓肠肌,检测腓肠肌湿重及收缩功能。结果对照组、实验组与空白组相比,腓肠肌湿重、单次收缩最大张力、强直收缩最大张力显著下降,差异有显著性意义(P＜0．05),产生收缩、单次最大收缩和最大强直收缩的域值均显著下降,差异有显著性意义(P＜0．05)。实验组的腓肠肌湿重、单次收缩最大张力、强直收缩最大张力均优于对照组,差异有显著性意义(P＜0．05),产生收缩、单次最大收缩和最大强直收缩的刺激强度均显著高于对照组,差异有显著性意义(P＜0．05)。结论局部注射HGF能显著提高大鼠废用性萎缩腓肠肌的收缩功能和肌肉湿重,对防治骨骼肌的废用性萎缩有明显效果。