Increased Hepatocyte Growth Factor Levels Research Articles

Evidence for platelet-derived transforming growth factor β1 as an early inducer of liver regeneration after hepatectomy in mice.

Platelets play a crucial role in tissue regeneration, and their involvement in liver regeneration is well-established. However, the specific contribution of platelet-derived Transforming Growth Factor Beta 1 (TGFβ1) to liver regeneration remains unexplored. This study investigated the role of platelet-derived TGFβ1 in initiating liver regeneration following 2/3 liver resection. Using platelet-specific TGFβ1 knockout (Plt.TGFβ1 KO) mice and wild-type littermates (Plt.TGFβ1 WT) as controls, the study assessed circulating levels and hepatic gene expression of TGFβ1, Platelet Factor 4 (PF4), and Thrombopoietin (TPO) at early time points post-hepatectomy (post-PHx). Hepatocyte proliferation was quantified through Ki67 staining and PCNA expression in total liver lysates at various intervals, and phosphohistone-H3 (PHH3) staining was employed to mark mitotic cells. Circulating levels of hepatic mitogens, Hepatocyte Growth Factor (HGF), and Interleukin-6 (IL6) were also assessed. Results revealed that platelet-TGFβ1 deficiency significantly reduced total plasma TGFβ1 levels at 5 h post-PHx in Plt.TGFβ1 KO mice compared to controls. While circulating PF4 levels, liver platelet recruitment and activation appeared normal at early time points, Plt.TGFβ1 KO mice showed more stable circulating platelet numbers with higher numbers at 48 h post-PHx. Notably, hepatocyte proliferation was significantly reduced in Plt.TGFβ1 KO mice. The results show that a lack of TGFβ1 in platelets leads to an unbalanced expression of IL6 in the liver and to strongly increased HGF levels 48 h after liver resection, and yet liver regeneration remains reduced. The study identifies platelet-TGFβ1 as a regulator of hepatocyte proliferation and platelet homeostasis in the early stages of liver regeneration.

Potential of circulating receptor-interacting protein kinase 3 levels as a marker of acute liver injury

The pathogenesis of acute liver failure (ALF) involves cell death. Necroptosis is a newly suggested programmed cell death, and receptor-interacting protein kinase 3 (RIPK3) has been reported as a marker for necroptosis. However, there are few reports on necroptosis in ALF. Therefore, we evaluated the role of cell death markers such as cytokeratin (CK) 18, cleaved CK (cCK) 18, and RIPK3 in ALF, as well as cytokines and hepatocyte growth factor (HGF). Seventy-one hospitalized patients with acute liver injury (38 nonsevere hepatitis [non-SH]/22 severe hepatitis [SH]/11 ALF) were studied. No significant difference was found for cytokines, but a substantial increase in HGF levels was found following the severity of hepatitis. The non-SH group had lower levels of CK18 and cCK18 than the SH/ALF group. RIPK3 was significantly lower in the non-SH/SH group than in the ALF group. HGF, RIPK3, and albumin levels were found to be important predictive variables. The present study suggests that cCK18, CK18, and RIPK3 are associated with the severity of hepatitis. RIPK3 and other markers related cell death may be useful for understanding the pathogenesis of ALF and as a prognostic marker of acute liver injury.

Myofibroblasts: A key promoter of tumorigenesis following radiofrequency tumor ablation.

Radiofrequency ablation (RFA) of intrahepatic tumors induces distant tumor growth through activation of interleukin 6/signal transducer and activator of transcription 3 (STAT3)/hepatocyte growth factor (HGF)/tyrosine-protein kinase Met (c-MET) pathway. Yet, the predominant cellular source still needs to be identified as specific roles of the many types of periablational infiltrating immune cells requires further clarification. Here we report the key role of activated myofibroblasts in RFA-induced tumorigenesis and successful pharmacologic blockade. Murine models simulating RF tumorigenic effects on a macrometastatic tumor and intrahepatic micrometastatic deposits after liver ablation and a macrometastatic tumor after kidney ablation were used. Immune assays of ablated normal parenchyma demonstrated significantly increased numbers of activated myofibroblasts in the periablational rim, as well as increased HGF levels, recruitment other cellular infiltrates; macrophages, dendritic cells and natural killer cells, HGF dependent growth factors; fibroblast growth factor-19 (FGF-19) and receptor of Vascular Endothelial Growth Factor-1 (VEGFR-1), and proliferative indices; Ki-67 and CD34 for microvascular density. Furthermore, macrometastatic models demonstrated accelerated distant tumor growth at 7d post-RFA while micrometastatic models demonstrated increased intrahepatic deposit size and number at 14 and 21 days post-RFA. Multi-day atorvastatin, a selective fibroblast inhibitor, inhibited RFA-induced HGF and downstream growth factors, cellular markers and proliferative indices. Specifically, atorvastatin treatment reduced cellular and proliferative indices to baseline levels in the micrometastatic models, however only partially in macrometastatic models. Furthermore, adjuvant atorvastatin completely inhibited accelerated growth of macrometastasis and negated increased micrometastatic intrahepatic burden. Thus, activated myofibroblasts drive RF-induced tumorigenesis at a cellular level via induction of the HGF/c-MET/STAT3 axis, and can be successfully pharmacologically suppressed.

Resveratrol inhibited hepatocyte apoptosis and alleviated liver fibrosis through miR-190a-5p /HGF axis

BackgroundHepatocyte apoptosis plays an important role in the progression of liver fibrosis. Overexpression of HGF (Hepatocyte growth factor) can reduce hepatocyte apoptosis and alleviate liver fibrosis. Our study aims to investigate whether resveratrol (Res) can alleviate liver fibrosis through miR-190a-5p /HGF axis. MethodsThe TGF-β1 (transforming growth factor-β1)-induced primary hepatocyte model in vitro and CCl4-induced liver fibrosis model in vivo were established. Hepatocyte apoptosis was determined by flow cytometry and TdT-mediated dUTP nick-end labeling (TUNEL) assay. HE (hematoxylin and eosin) staining and Sirius red staining were performed to observe the pathological changes of the liver tissues. Western blotting was used to determine the expression of apoptosis-associated proteins and HGF. Quantitative Real-time PCR (QRT-PCR) was used to quantify miR-190a-5p expression. The dual-luciferase reporter assay was performed to verify the targeting relationship between miR-190a-5p and HGF. ResultsHepatocyte apoptosis and miR-190a-5p expression level were increased in TGF-β1-induced cell models in vitro while the results were reversed after treatment with Res. Besides, miR-190a-5p negatively regulated HGF expression, and miR-190a-5p regulated hepatocyte apoptosis by targeting HGF. Res reduced the apoptosis of hepatocytes and the effect was achieved by decreasing the expression levels of miR-190a-5p and increasing HGF expression in vitro. Moreover, experiments in vivo verified that Res reduced apoptosis of the hepatocytes reduced AST, and ALT levels, as well as raised Albumin levels in the serum. Apart from that, Res decreased the expression ofmiR-190a-5p and increased HGF levels at the same time, and further reduced liver fibrosis. ConclusionIn summary, our study indicated that Res could inhibit the up-regulation of miR-190a-5p caused by CCl4 or TGF-β1. And then the decreased miR-190a-5p could further lessen the hepatocyte apoptosis by increasing HGF levels and finally relieving liver fibrosis.

Efficacy of autologous bone marrow mononuclear cell transplantation in dogs with chronic spinal cord injury.

Background:Spinal cord injury (SCI) is relatively common in dogs and is a devastating condition involving loss of sensory neurons and motor neurons. However, the main clinical protocol for the management of SCI is surgery to decompress and stabilize the vertebra. Cell transplantation therapy is a very promising strategy for the treatment of chronic SCI, but extensive preclinical and clinical research work remains.Aim:The aim of this study is to confirm the effect of bone marrow-derived mononuclear cell (BM-MNC) transplantation for chronic SCI in dogs.Methods:We tested the treatment efficiency of chronic SCI in 12 dogs using BM-MNC transplantation. Neurological evaluation used the Texas Spinal Cord Injury Scale (TSCIS). Concurrently, we characterized the transplanted cells by evaluation using quantitative real-time polymerase chain reaction, flow cytometry, and enzyme-linked immunosorbent assay.Result:All dogs had a pre-transplantation TSCIS score of 0. Two animals did not show any improvement in their final TSCIS scores. The remaining 10 dogs (83.4%) achieved improvement in the final TSCIS scores. Five of them (41.7%) regained ambulatory function with a TSCIS score greater than 10. We determined that canine BM-MNCs expressed hepatocyte growth factor (HGF) mRNA at higher levels than other cytokines, with significant increases in HGF levels in cerebrospinal fluid within 48 hours after autologous BM-MNC transplantation into the subarachnoid space of the spinal dura matter in dogs.Conclusions:BM-MNC transplantation may be effective for at least some cases of chronic SCI.

Elevated plasma levels of hepatocyte growth factor in rats experimentally envenomated with Bothrops jararaca venom: Role of snake venom metalloproteases

The hepatocyte growth factor (HGF)/c-met pathway, which mainly consists of HGF activator (HGFA) and its substrate HGF, protects various types of cells via anti-apoptotic and anti-inflammatory signals. Thrombin is the main physiological activator of such plasmatic pathway, and increased plasma concentrations of HGF have been considered as a molecular marker for some pathological conditions, such as disseminated intravascular coagulation. Since thrombin generation is often linked to tissue injury, and these events are common during snake venom-induced consumption coagulopathies (VICC), our goals were to examine whether Bothrops jararaca venom (Bjv), which induces VICC in vivo: (i) activates the HGF/c-met pathway in vivo and (ii) cleaves zymogen forms of HGFA and HGF (proHGFA and proHGF, respectively) in vitro. Two experimental groups (n = 6, each) of male adult Wistar rats were subcutaneously injected with 500 μL of 0.9% NaCl solution (control) or sub-lethal doses (1.6 mg/kg) of Bjv. Three hours after envenomation, whole blood samples were collected from the carotid arteries to evaluate relevant coagulation parameters using rotational thromboelastometry and fibrinogen level (colorimetric assay). Additionally, the plasma concentration of HGF was assayed (ELISA). Thromboelastometric assays showed that blood clotting and fibrin polymerization were severely impaired 3 h after Bjv injection. Total plasma HGF concentrations were almost 6-fold higher in the Bjv-injected group (410.0 ± 91) compared with control values (68 ± 18 pg/mL, p < 0.05). Western blotting assay showed that Bjv processed proHGFA and proHGF, generating bands resembling those generated by thrombin and kallikrein, respectively. In contrast to the serine protease inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF), the metalloprotease inhibitor ethylenediaminetetraacetic acid disodium salt (Na2-EDTA) strongly reduced the ability of Bjv to process proHGFA and generated one active band similar to that of thrombin. Since Bjv contains prothrombin and factor X activators, increased intravascular thrombin formation might partly explain the increased HGF levels after bothropic envenomation. In conclusion, these findings suggest that snake venom metalloproteases may be determinant for elevation of plasma levels of HGF in rats experimentally envenomated with Bjv.

Hepatocyte growth factor as a long‑term predictor for total and cardiovascular mortality in patients on peritoneal dialysis

Hepatocyte growth factor (HGF) is a regenerative protein involved in tissue protection and endothelial repair in response to injury. The aim of the study was to assess the effect of increased HGF levels on total and cardiovascular (CV) mortality in patients on peritoneal dialysis (PD) during 6‑year follow‑up. The study included 55 patients (mean age, 53 years; median duration of PD, 24 months). The ejection fraction (EF) and calcium score (CaSc) were measured. White blood cell (WBC) count and albumin, calcium (Ca), phosphorus (Pi), intact parathormone (iPTH), and high‑sensitivity C‑reactive protein (hsCRP) levels were measured. Serum levels of HGF, interleukin (IL) 6, and IL‑18 were determined using enzyme‑linked immunosorbent assays. Of all patients, 45% died within 6 years, including 80% from CV complications. HGF significantly correlated with the total (hazard ratio [HR], 1.97; P = 0.03) and CV (HR, 2.04; P = 0.04) mortality in a univariate Cox regression model. This was confirmed by a multiple model including age, dialysis duration, residual renal function (RRF), albumin, Ca × Pi, EF, and CaSc (HR, 2.24; P = 0.02 and HR, 2.58; P = 0.02 for total and CV mortality, respectively). Factors negatively affecting patients' survival included WBC count, hsCRP, IL‑6, and CaSc, while higher albumin levels and EF were associated with longer overall survival. HGF positively correlated with WBC count (r = 0.30, P = 0.01), hsCRP (r = 0.25, P = 0.04), IL‑6 (r = 0.46, P = 0.0004), CaSc (r = 0.29, P = 0.03), and mean arterial pressure (r = 0.25; P = 0.04) and negatively with RRF (r = -0.31, P = 0.02). Increased concentrations of proinflammatory cytokines and an association between HGF levels and CaSc may indicate higher total and CV mortality in patients on PD.

Insulin-Resistance-Associated Compensatory Mechanisms of Pancreatic Beta Cells: A Current Opinion

Insulin-Resistance-Associated Compensatory Mechanisms of Pancreatic Beta Cells: A Current Opinion

Hepatocyte Growth Factor Plays a Key Role in Insulin Resistance-Associated Compensatory Mechanisms

Insulin resistance is present in obesity and in type 2 diabetes and is associated with islet cell hyperplasia and hyperinsulinemia, but the driving forces behind this compensatory mechanism are incompletely understood. Previous data have suggested the involvement of an unknown circulating insulin resistance-related β-cell growth factor. In this context, looking for candidates to be a circulating factor, we realized that hepatocyte growth factor (HGF) is a strong candidate as a link between insulin resistance and increased mass of islets/hyperinsulinemia. Our approach aimed to show a possible cause-effect relationship between increase in circulating HGF levels and compensatory islet hyperplasia/hyperinsulinemia by showing the strength of the association, whether or not is a dose-dependent response, the temporality, consistency, plausibility, and reversibility of the association. In this regard, our data showed: 1) a strong and consistent correlation between HGF and the compensatory mechanism in three animal models of insulin resistance; 2) HGF increases β-cell mass in a dose-dependent manner; 3) blocking HGF shuts down the compensatory mechanisms; and 4) an increase in HGF levels seems to precede the compensatory response associated with insulin resistance, indicating that these events occur in a sequential mode. Additionally, blockages of HGF receptor (Met) worsen the impaired insulin-induced insulin signaling in liver of diet-induced obesity rats. Overall, our data indicate that HGF is a growth factor playing a key role in islet mass increase and hyperinsulinemia in diet-induced obesity rats and suggest that the HGF-Met axis may have a role on insulin signaling in the liver.

Abstract PR6: Widespread potential for growth factor-driven resistance to anti-cancer kinase inhibitors

Abstract Mutationally activated kinases, including EGFR, HER2, ALK, ABL, PDGFR, c-KIT, and BRAF, define a clinically validated class of targets for cancer drug therapy. However, the efficacy of kinase inhibitors in patients whose tumors harbor such alleles is invariably limited by innate or acquired drug resistance. As molecular mechanisms of resistance have begun to be elucidated, a recurrent theme is the engagement of survival signals redundant to those transduced by the targeted oncogenic kinase. Cancer cells typically express multiple receptor tyrosine kinases (RTKs), and many of these can potentially mediate signals that converge on common and critical downstream cell survival effectors - most notably, PI-3 kinase (PI3K) and MAP kinase (MAPK). Consequently, an increase in RTK ligand levels, via autocrine tumor cell production, paracrine contribution by tumor stroma, or systemic production, could confer resistance to inhibitors of an oncogenic kinase with a similar downstream signaling output. Indeed, using a large panel of kinase-“addicted” cancer cell lines, we found that the vast majority of such cells can be “rescued” from drug sensitivity by simply exposing them to one or more RTK ligands that engage redundant survival effectors. Among the findings with immediate clinical implications was the observation that hepatocyte growth factor (HGF) confers resistance to the HER2 kinase inhibitor lapatinib in HER2 amplified breast cancer cells, and to the BRAF inhibitor PLX4032 (vemurafenib) in BRAF mutant melanoma cells. Analysis of systemic HGF levels from PLX4032-treated BRAF mutant metastatic melanoma patients who were enrolled on the BRIM2 study indicated that increased HGF levels were significantly associated with a worse clinical outcome. These observations highlight the extensive redundancy of RTK-transduced signaling in cancer cells and the potentially broad role of widely expressed RTK ligands in both innate and acquired resistance to drugs targeting oncogenic kinases. This proffered talk is also presented as Poster B38.

Abstract 9122: Heparin Mobilizes Multipotent Human Mesoangioblasts

The identification of clinically applicable drugs which mobilize endogenous mesenchymal progenitor cells may offer novel therapeutic application in cardiovascular diseases. We recently showed that hepatocyte growth factor (HGF) induces the mobilization of multipotent circulating mesenchymal cells that co-express endothelial markers (so-called circulating mesoangioblasts, cMABs). Since HGF only has a short half life, we investigated whether heparin might be useful to endogenously increase HGF levels thereby inducing the mobilization of cMABs. Heparin was infused in patients with coronary artery disease at a concentration of 200 U/kg (n=11 patients) and 300 U/kg (n=11 patients) and serum HGF levels were determined by ELISA. Consistent with published studies, heparin dose-dependently increased HGF levels to 34.4+1.9 in patients receiving 200U/kg heparin and 42.8+0.9 ng/ml in the patients treated with 300 U/kg. Moreover, heparin dose-dependently increased the number of circulating mesenchymal cell colonies. Patients receiving 200U/kg showed 0.30+0.12 colonies / mononuclear cells (x10 6 ). Further increasing the heparin dosage to 300U/kg increased the number of colonies to 0.63+0.17 colonies / mononuclear cells (x10 6 ). In contrast, we were never able to obtain colonies in patients receiving heparin concentrations below 100 U/kg. The mesenchymal origin of the colonies was characterised by the lack of hematopoietic progenitor cell markers CD45 and CD34. Consistent with the original characterisation of the mesoangioblasts, the colonies expressed the mesenchymal marker CD73, the HGF-receptor c-Met as well as the endothelial marker KDR. In conclusion, we demonstrate that heparin can dose-dependently mobilize mesenchymal progenitor cells in humans. These findings might open up an avenue to non-invasively obtain multipotent mesenchymal cells for therapeutic application in patients with cardiovascular disease.

Estradiol modulation of hepatocyte growth factor by stromal fibroblasts in the female reproductive tract

Primary human uterine, cervical, and ectocervical stromal fibroblasts constitutively secrete hepatocyte growth factor (HGF), yet only uterine stromal fibroblasts increase HGF secretion in response to estradiol. Estradiol-induced HGF secretion by uterine stromal fibroblasts may have a significant effect on uterine cancer and endometriosis.

Stimulation by glutamine and proline of HGF production in hepatic stellate cells

Amino acids regulate cellular functions in a variety of cell types. Most notably, leucine stimulates protein production through the mammalian target of rapamycin (mTOR)-dependent signaling pathway. We investigated the effect of amino acids on hepatocyte growth factor (HGF) production. Treatment with glutamine and proline, as well as leucine, increased HGF levels in the culture medium of a rat hepatic stellate cell clone in a dose-dependent manner. Up-regulation of phosphorylation of 70 kDa ribosomal protein S6 kinase and eukaryotic initiation factor 4E-binding protein 1 was not apparent in the cells after treatment with glutamine or proline. When rats received injections of glutamine or proline, hepatic and circulating HGF levels increased and peaked around 12 h after treatment. Glutamine and proline may have the potential to stimulate HGF production but the mechanism underlying this stimulation seems not to be through the mTOR-dependent signaling pathway.

Stability of faecal hepatocyte growth factor determination

In order to evaluate the accuracy and reproducibility of determination of hepatocyte growth factor (HGF) levels in faeces, the stability of HGF in samples processed in different ways was investigated. An ELISA method was used for determination of HGF concentrations. Faeces samples from healthy controls and patients with infectious diarrhoea were studied. It was found that faeces HGF concentration remained stable irrespective of whether samples were freeze‐thawed several times, kept for 6, 12 or 24 h at room temperature or refrigerated for 6, 12, 24 or 36 h; the levels of HGF did not change significantly when samples were freeze‐dried. Adding protease inhibitor to the faeces samples did not affect the HGF levels. There were no significant differences between HGF levels using phosphate buffered saline (PBS) (pH 7.4) or NaCL as buffer, but it was observed that levels of HGF were significantly lower in the samples that were diluted in distilled water. Although both HGF and albumin through various mechanisms may increase in faeces during infectious diarrhoea, there was no significant correlation between faeces HGF levels and albumin levels, which might indicate local production of HGF in the bowel in response to infection. It is concluded that determination of faeces HGF levels is feasible with a high degree of stability. Increased HGF levels in faeces might represent a local production of HGF during bowel injury and might be of use as a diagnostic and monitoring assay.

Treatment with leucine stimulates the production of hepatocyte growth factor in vivo

Hepatocyte growth factor (HGF) has pleiotropic effects. Up-regulation of HGF activity in vivo may be beneficial. Branched-chain amino acids (BCAAs) are known to modulate various cellular functions. When starved rats received intraperitoneal injections of valine, leucine or isoleucine, only leucine treatment increased both hepatic and circulating levels of HGF in a dose-dependent manner, up to 1.5 and 2.3 times higher, respectively, than in controls. When young growing rats with free access to food were injected with leucine once a day for a week, HGF levels and liver weights were significantly higher than those of control rats. Furthermore, 1 week of leucine treatment of adult rats resulted in elevated serum albumin levels with an increase in HGF levels. Taken together with our previous report showing that leucine stimulates HGF production by hepatic stellate cells in culture, leucine, among BCAAs, may induce an increase in HGF production by the liver in vivo.

Hepatocyte growth factor treatment ameliorates diarrhea and bowel inflammation in a rat model of inflammatory bowel disease

Background/purpose Transfection of the HLA-B27 gene into normal Fischer rats induces phenotypic changes similar to inflammatory bowel disease (IBD). This study investigated the benefits of 2 doses of hepatocyte growth factor (HGF) on the manifestations of IBD in this rat model. Methods Fischer rats and HLA-B27 rats were divided into 4 groups: Fischer rats treated with saline, HLA-B27 rats treated with saline, HGF at 150 μg/kg/d, and HGF at 300 μg/kg/d. HGF or saline was infused for 14 days via an osmotic pump attached to a catheter in the internal jugular vein. After treatment, rats were evaluated for diarrhea and reduction in gross and microscopic bowel inflammation. Statistics were determined using analysis of variance (ANOVA). A P value ≤ .05 was considered significant. Results Administration of HGF at 150 μg/kg/d decreased diarrhea by 40%, gross inflammation by 41%, and microscopic inflammation by 72% ( P ≤ .05). At 300 μg/kg/d HGF decreased diarrhea by 46%, gross inflammation by 45%, and microscopic inflammation by 54% (P ≤ .05). Conclusions HGF administration reduces the clinical manifestations of IBD in this rat model. Similar effects were seen at both doses of HGF administration, implying that there is a plateau above which further increases in HGF levels provides no added benefit. HGF administration may be clinically useful in the management of IBD.

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

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). 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. 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. 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 predicts survival and relates to inflammation and intima media thickness in end-stage renal disease

Hepatocyte growth factor (HGF) is a pleiotropic cytokine involved in tissue protection and repair in the endothelium and various organ systems. The serum concentration of this protein is markedly increased in patients with chronic renal diseases, but the clinical and pathophysiological correlates of this substance in renal failure are scarcely understood. Serum HGF, lipid, albumin, hemoglobin, C-reactive protein (CRP), and immunoglobulin G (IgG) were measured in fasting conditions in a cohort of 244 dialysis patients. In addition, the relationship between HGF and severity of carotid atherosclerosis was studied in a subgroup of 105 patients. The entire cohort was followed up for a median of 31 months (interquartile range, 21 to 34 months). Serum HGF level was directly related to duration of dialysis treatment, CRP level, age, IgG level, and hemoglobin level and inversely related to systolic and diastolic arterial blood pressure. In a multiple regression model, only duration of dialysis treatment (r = 0.38), age (r = 0.26), hemoglobin level (r = 0.17), IgG level (r = 0.15), and CRP level (r = 0.14) were independent correlates of serum HGF level (R = 0.54; P < 0.0001), suggesting that increased levels of serum HGF may be the expression of a chronic inflammatory process. HGF levels were greater in hemodialysis than continuous ambulatory peritoneal dialysis patients, independent of the type of dialysis membrane, and slightly increased in patients seropositive for hepatitis C virus. In the subgroup of patients who underwent echo color Doppler studies, serum HGF level was an independent correlate of intima media thickness (IMT; partial r = 0.23; P = 0.02). In the entire cohort, increased HGF levels predicted shorter survival in a multivariate Cox regression model. These results support the hypothesis that in patients with chronic renal failure, increased serum HGF level is linked to an inflammatory state. The relationships between HGF level and survival and IMT suggest that this cytokine might be a marker of a process that has a major impact in the high mortality and morbidity of the dialysis population.

INCREASE IN THE CIRCULATING LEVEL OF HEPATOCYTE GROWTH-FACTOR IN BREAST-CANCER PATIENTS WITH DISTANT METASTASES

Hepatocyte growth factor (HGF) is known to be a potent mitogen not only for hepatocytes but also for a variety of cell types including tumor cells and endothelial cells. However, still little is known about the circulating level of HGF in cancer patients. We measured the HGF level in sera in 61 breast cancer patients including 31 primary breast cancer patients and 30 recurrent breast cancer patients by an enzyme linked immunosorbent assay system. In 10 (32.3%) out of 31 primary breast cancer patients and in 25 (83.3%) out of 30 recurrent breast cancer patients, the circulating level of HGF was increased to over 0.4 ng/ml. In particular, the increase in the level of HGF was marked in patients with liver metastases (mean+/-SD: 1.286+/-0.557 ng/ml) compared to those with recurrence of other sites (mean+/-SD: 0.635+/-0.277 ng/ml). It was suggested that the increase in HGF level in sera might be associated with tumor progression, particularly with liver metastases, in human breast cancer.