Hepatocyte growth factor and vascular endothelial growth factor in ischaemic heart disease

BACKGROUND: Hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) are endothelial cell-specific growth factors, but the production of these growth factors in cardiomyocytes has also been demonstrated. However, there have been no reports focusing their attention on the changes in these growth factors after coronary intervention. We investigated the time-course changes of the serum VEGF and HGF levels in angina pectoris (AP) and acute myocardial infarction (AMI). METHODS: The serum HGF and VEGF levels were measured in 60 patients with AP, in 62 patients with AMI (AP, before heparin administration, and at 24 and 48 hours, and one week after intervention; AMI, before heparin, and at 48 and 72 hours, and one, two, three and four weeks) and in 56 patients with neurocirculatory asthenia as controls. We defined the patients with remodelling who showed an increase in left ventricular end-diastolic volume index (LVEDVI) in the sub-acute phase of AMI. RESULTS: Hepatocyte growth factor levels in the AP and AMI were significantly higher than that in the control (p<0.0001). The AMI level was also significantly higher than AP (p<0.001). In the AMI and AP, HGF peaked at 48 hours. Vascular endothelial growth factor level in the AMI was significantly higher than that in the control and AP (p<0.0001). In the AMI, VEGF peaked at two weeks. There was a significant positive correlation between the peak VEGF and LVEDVI in the sub-acute phase of AMI (p=0.0089, r=0.436). Peak VEGF in the remodelling (+) group was significantly higher than that in the remodelling (-) group (p<0.001). In the AP, VEGF was unchanged. CONCLUSION: While both myocardial and vascular damage contribute to an increase in HGF level, vascular damage is not associated with the increase in VEGF. Vascular endothelial growth factor might be related to left ventricular remodelling in the sub-acute phase of myocardial infarction.     

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.     

Hepatocyte growth factor and lung fibrosis

Idiopathic pulmonary fibrosis is currently believed to be driven by alveolar epithelial cells, with abnormally activated alveolar epithelial cells accumulating in an attempt to repair injured alveolar epithelium (1). Thus, targeting the alveolar epithelium to prevent or inhibit the development of pulmonary fibrosis might be an interesting therapeutic option in this disease. Hepatocyte growth factor (HGF) is a growth factor for epithelial and endothelial cells, which is secreted by different cell types, especially fibroblasts and neutrophils. HGF has mitogenic, motogenic, and morphogenic properties and exerts an antiapoptotic action on epithelial and endothelial cells. HGF has also proangiogenic effect. In vitro, HGF inhibits epithelial-to-mesenchymal cell transition and promotes myofibroblast apoptosis. In vivo, HGF has antifibrotic properties demonstrated in experimental models of lung, kidney, heart, skin, and liver fibrosis. Hence, the modulation of HGF may be an attractive target for the treatment of lung fibrosis.     

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.     

肝细胞生长因子与肺动脉栓塞

肝细胞生长因子(HGF)是一种多功能细胞因子,近年研究发现,HGF系统在肺动脉栓塞的表达异常,提示HGF系统参与肺栓塞的发生、发展过程。HGF在肺缺血损伤早期增高,可作为肺栓塞的早期生物标记物;HGF在肺缺血-再灌注后损伤肺再生中起保护作用,是肺泡上皮细胞最强有力的促有丝分裂原,并诱导肺毛细血管发生,减轻进展期肺动脉高压;但HGF对肺动脉栓塞患者预后的价值目前未见相关报道。     

Hepatocyte growth factor (HGF) in stable and unstable coronary heart disease

Hepatocyte growth factor (HGF) is an angiogenic factor upregulated in ischaemic diseases. We measured plasma HGF concentration in 26 patients (pts) with stable angina pectoris (SAP) and 16 pts with unstable angina pectoris (UAP). HGF levels were significantly higher in pts with UAP compared with pts with SAP (p<0,01), in pts with SAP vs control group (n=38, p<0,01) and in pts with UAP vs control group (p<0,001). HGF levels in SAP group correlated with heart failure symptoms (p=0,023). There was a trend towards significance between HGF and left ventricle ejection fraction (p=0,08) and between HGF and VEGF levels in pts with SAP (p=0,08). This study demonstrates that HGF plasma levels correlates with SAP symptoms. Pts with SAP and UAP has significantly higher levels of HGF comparing with control group.     

Hepatocyte growth factor as a hematopoietic regulator

Hepatocyte growth factor (HGF) was originally isolated as a mitogen for adult hepatocytes, but this cytokine is now regarded as a multi- functional factor. In the present study, we show that the mouse liver in the middle and/or late stage of the fetal life expresses both HGF and c-met (its receptor) messages. HGF and c-met mRNA are coexpressed not only in the adherent layers of fetal liver long-term cultures (FL- LTCs) and adult bone marrow long-term cultures (BM-LTCs), but also in the stromal cell lines MS-5 and PA-6. Addition of human HGF (2 and 20 ng/mL) to the LTCs enhances (1) nonadherent cell counts (ninefold in FL- LTCs and sixfold in BM-LTCs), (2) nonadherent colony-forming unit-in culture (CFU-C) counts (eightfold in FL-LTCs and fivefold in BM-LTC), and (3) cobblestone colony counts. However, HGF slightly inhibits the proliferation of stromal cells. No direct effect of HGF on freshly isolated BM and/or FL cells is found in the CFU-C assay. However, an approximately 1.5-fold synergistic increase in CFU-C counts is noted when the BM or FL cells are cocultured with HGF in the presence of interleukin-3. These findings strongly suggest that HGF plays a crucial role as a hematopoietic regulator in the proliferation and differentiation of hematopoietic progenitors.     

Hepatocyte growth factor measurement in AL amyloidosis

Hepatocyte growth factor (HGF) is a pro-angiogenic cytokine activated by tissue-type plasminogen activator (tPA) that might play a role in the progression of multiple myeloma (MM). Preliminary studies indicated that serum HGF levels were higher in patients with AL amyloidosis (AL) compared to those with MM. The aim of the present study was to determine whether HGF is a relevant marker of diagnosis and prognosis in AL. HGF serum levels were measured at diagnosis in patients with monoclonal gammopathy (MG) without AL (76 controls), or with biopsy-proven systemic AL (69 patients). HGF serum levels were significantly higher in patients with AL compared to controls, respectively, 11.2?ng/mL [min: 0.95–max: 200.4] versus 1.4?ng/mL [min: 0.82–max: 6.2] (p?<?0.0001). The threshold value of 2.2?ng/mL conferred optimal sensitivity (88%) and specificity (95%) to differentiate AL and monoclonal gammopathy of undetermined significance (MGUS) patients. Serum HGF concentrations were correlated positively with the severity of cardiac involvement and the serum level of monoclonal light chains. These data suggest that HGF measurement could be used in patients with MG to detect AL or to reinforce a clinical suspicion of AL and to guide indications for diagnostic tissue biopsies.     

肝细胞生长因子与特发性肺纤维化

特发性肺纤维化（idiopathic pulmonary fibrosis，IPF）是一种原因不明的慢性肺部疾患，以肺间质纤维化为主要特征，其发病隐匿，进展迅速，病死率高。从发病后到死亡，IPF患者的平均生存时间为3～5年。目前对于IPF的治疗仍然是以糖皮质激素和免疫抑制剂药物为主，但疗效不佳。已有的研究表明：糖皮质激素治疗1PF的有效率小于30％，合用免疫抑制剂后不但会引起严重的不良反应，而且也不能有效降低IPF患者的病死率。这些都似乎说明炎细胞的浸润并不是导致IPF发病的原因，而是继发于IPF的一种炎症反应。随着对IPF发病机制研究的不断深入，许多新的治疗方法与药物正逐步受到医学界的重视，肝细胞生长因子（hepatocyte growth factor，HGF）便是其中一种。本文概述了近年来对HGF在IPF治疗中的研究进展。     

Hepatocyte growth factor: clinical implications in hepatobiliary pancreatic surgery

Hepatocyte growth factor (HGF), originally identified as the most potent mitogen for hepatocytes, is now known to be a cytokine with numerous functions in a wide variety of cells. HGF transduces its various activities via a receptor encoded by the c-met proto-oncogene and coupled to a number of transducers integrating the HGF signal inside the target cells. Extensive investigation has revealed that HGF has various beneficial effects, especially for liver. HGF significantly stimulates regeneration in damaged, as well as in normal liver, ameliorates hepatic fibrosis/cirrhosis; and attenuates various types of liver dysfunction in animals. Moreover, the fascinating data on HGF in experimental liver and islet transplantation suggest that the use of HGF may represent a breakthrough for reducing the shortage of donor livers, and increasing the success rate of insulin independence after islet transplantation. Further understanding of the biological significance of HGF, including that in carcinogenesis, will undoubtedly have important clinical implications in hepatobiliary pancreatic surgery.     

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.     

Hepatocyte growth factor levels in Legionella pneumonia: A retrospective study

Background

Typhoid fever remains a significant health problem in many developing countries. A rapid test with a performance comparable to that of blood culture would be highly useful. A rapid diagnostic test for typhoid fever, Tubex^®, is commercially available that uses particle separation to detect immunoglobulin M directed towards Salmonella Typhi O9 lipopolysaccharide in sera.

Methods

We assessed the sensitivity and specificity of the Tubex test among Tanzanian children hospitalized with febrile illness using blood culture as gold standard. Evaluation was done considering blood culture confirmed S. Typhi with non-typhi salmonella (NTS) and non - salmonella isolates as controls as well as with non-salmonella isolates only.

Results

Of 139 samples tested with Tubex, 33 were positive for S. Typhi in blood culture, 49 were culture-confirmed NTS infections, and 57 were other non-salmonella infections. Thirteen hemolyzed samples were excluded. Using all non - S. Typhi isolates as controls, we showed a sensitivity of 79% and a specificity of 89%. When the analysis was repeated excluding NTS from the pool of controls we showed a sensitivity of 79% and a specificity of 97%. There was no significant difference in the test performance using the two different control groups (p > 0.05).

Conclusion

This first evaluation of the Tubex test in an African setting showed a similar performance to those seen in some Asian settings. Comparison with the earlier results of a Widal test using the same samples showed no significant difference (p > 0.05) for any of the performance indicators, irrespective of the applied control group.     

Hepatocyte growth factor promotes migration of human myeloma cells

Multiple myeloma is characterized by the accumulation and dissemination of malignant plasma cells in the bone marrow. Cell migration is thought to be important for these events. We studied migration in a Transwell two-chamber assay and tested the motogenic effect of various cytokines. In addition to insulin-like growth factor-1 and stromal cell-derived growth factor-1alpha, previously known as chemoattractants for myeloma cells, we identified hepatocyte growth factor as a potent attractant for myeloma cells. Hepatocyte growth factor-mediated migration was dependent on phosphatidylinositol-3-kinase, involved the MAPK/Erk signaling cascade and VLA-4 integrins, but did not involve Akt, mTOR or G proteins.     

Hepatocyte growth factor accelerates restitution of intestinal epithelial cells

Many cytokines are involved in the repair of damaged tissue, and one of these, hepatocyte growth factor (HGF), is involved not only with liver regeneration but also in the repair of other tissues. To investigate the importance of HGF in the repair of the small intestine, we evaluated its effect and that of other growth factors in IEC-6 cells, an intestinal epithelial cell line derived from normal rat small intestine. Round "wounds" were made in confluent monolayers of IEC-6 by silicon rubber-tipped steel rods and various cytokines; transforming growth factor α (TGF-α), transforming growth factor β1 (TGF-β1), keratinocyte growth factor (KGF), and HGF, were added. We photographed the repaired monolayers every 24 h and calculated the ratios of areas not covered by cells to initial areas. Cell proliferation with TGF-α, TGF-β, KGF, or HGF was examined in terms of [3H]-thymidine uptake. Finally, we determined c-met (the HGF receptor) mRNA in the IEC-6 cells by Northern blot hybridization. HGF was the most potent of the cytokines in accelerating repair of the damaged monolayer of IEC-6. HGF was also 1.34 times more effective than control the medium for inducing cell proliferation of IEC-6. By Northern blot hybridization, three bands of mRNA bound to c-met cDNA. These results suggest that HGF is important in the repair of the small intestine. (Received Feb. 21, 1997; accepted Aug. 22, 1997)