Soluble c-Met in serum of patients with multiple myeloma: correlation with clinical parameters

Objectives: The receptor tyrosine kinase c‐Met and its ligand, hepatocyte growth factor (HGF), play key roles in tumour genesis and metastasis and contribute in multiple myeloma pathogenesis. Substantial data support that a soluble extracellular fragment of c‐Met may function as a decoy receptor that downregulates the biological effects of HGF and c‐Met. We examined serum levels of soluble c‐Met in patients with myeloma and healthy individuals and investigated a possible relationship with clinical disease parameters and survival. Methods: The concentration of c‐Met and HGF was measured by enzyme‐linked immunosorbent assay in serum (n = 49) and bone marrow plasma (n = 16) from patients with multiple myeloma and in serum from healthy controls (n = 26). Results: The median serum concentration of soluble c‐Met was 186 ng/mL (range 22–562) in patients with multiple myeloma and 189 ng/mL (range 124–397) in healthy individuals. There was a significant negative correlation between serum c‐Met levels and disease stage, bone marrow plasma cell percentage and serum concentration of M‐protein. Conclusion: We have for the first time examined the concentration of soluble c‐Met in serum from patients with myeloma and found equal median levels in patients with myeloma as a group and healthy individuals. Still, serum levels of soluble c‐Met correlated negatively with parameters of disease burden in patients with myeloma. We suggest that a possible role for the c‐Met ectodomain as a negative regulator of HGF/c‐Met activity should be examined in multiple myeloma.     

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.     

Regeneration of injured intestinal mucosa is impaired in hepatocyte growth factor activator-deficient mice

BACKGROUND AND AIMS: Hepatocyte growth factor activator (HGFA) is a serum proteinase that specifically converts an inactive single-chain form of hepatocyte growth factor (HGF) into an active 2-chain form. HGFA is produced in its precursor form and then activated in injured tissues. To address the precise role of HGFA and to investigate the mechanisms of HGF activation in injured tissues, we generated mice deficient in HGFA. METHODS: HGFA-deficient mice were generated using targeted gene disruption. The regenerating process of intestinal mucosa damaged by oral administration of dextran sodium sulfate (DSS) or by rectal administration of acetic acid was examined in both HGFA-deficient and control mice. HGF processing activity was analyzed using Western blotting and an HGF activation assay. RESULTS: Homozygous mutant mice were viable and fertile without obvious abnormalities. When mice were treated with 3% DSS in drinking water for 6 days followed by distilled water without DSS, 72% of HGFA-deficient mice died through day 12 while 75% of control mice survived injury. Similar results were also observed in the acetic acid-induced intestinal injury; the survival rate was 36.6% in HGFA-deficient mice and 84.2% in control mice. In HGFA-deficient mice, the injured mucosa was not sufficiently covered by regenerated epithelium and the activation of HGF was impaired in the injured colon. CONCLUSIONS: These results indicate that HGFA is required for repair of injured intestinal mucosa but is not essential for normal development during embryogenesis or after birth.     

Hepatocyte growth factor in myeloma patients treated with high-dose chemotherapy

Hepatocyte growth factor (HGF) is a cytokine produced by myeloma cells. We examined serum HGF levels in a population of young myeloma patients (median age 52 years) treated with high-dose chemotherapy. Sera from 128 myeloma patients at diagnosis and serial samples from 16 patients were analysed. Compared with 62 healthy controls, HGF was elevated at diagnosis in 25% of patients (median 0.48 and 1.08 ng/ml respectively; P < 0.0001). The 95 patients who completed therapy were analysed for the impact of HGF on survival. Median survival was not reached after 77 months in the patient group with normal HGF values (< 1.7 ng/ml, n = 69). In the group with elevated HGF (>/= 1.7 ng/ml, n = 26), median survival was 63 months (P = 0.08). In 16 patients, serum was drawn at diagnosis and at the time of expected disease remission (6 weeks to 3 months after chemotherapy). HGF values declined after treatment in 14 of these patients, from a median of 0.9 ng/ml (0.49-1.65) to 0.42 ng/ml (0.32-0.73) (P = 0.005). Our results show that in young myeloma patients HGF is elevated, and that patients with higher levels had a trend towards poorer prognosis. Treatment with high-dose chemotherapy reduced HGF in the serum of the majority of patients.     

Clinical significance of vascular endothelial growth factor and hepatocyte growth factor in multiple myeloma

Angiogenesis is a crucial process in the progression of multiple myeloma (MM). Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are multifunctional cytokines that potently stimulate angiogenesis including tumour neovascularization. Serum levels of VEGF and HGF were measured in 52 patients with MM by enzyme-linked immunosorbent assay (ELISA). Serum levels of VEGF and HGF were elevated in MM patients compared with healthy controls (VEGF: mean 0.31 ng/ml and 0.08 ng/ml respectively, P < 0.01; HGF: mean 2.17 ng/ml and 0.45 ng/ml, respectively, P < 0.001). In serial samples taken after chemotherapy, serum VEGF and HGF levels were correlated with M-protein levels. Serum levels of VEGF were higher in patients with extramedullary plasmacytomas than in patients without them (P < 0.05). They were also significantly higher in a group of patients who showed poor response to chemotherapy (P < 0.01). Serum levels of HGF were higher in patients with complications such as anaemia, hypercalcaemia and amyloidosis than in patients without these complications (P < 0.01, P < 0.05, P < 0.05 respectively). Both serum VEGF and HGF levels were significant predictors of mortality (P = 0.01, P = 0.02, respectively, log-rank test). The present study demonstrated that serum levels of VEGF and HGF are significantly elevated and dependent on the severity of MM, suggesting that measurement of VEGF and HGF may be useful for assessing disease progression and for predicting the response to chemotherapy in MM patients.     

Elevated serum concentration of hepatocyte growth factor in patients with multiple myeloma: correlation with markers of disease activity

Hepatocyte growth factor (HGF) has been shown to be involved in angiogenesis, epithelial cell proliferation, and osteoclast activation. HGF and its receptor are expressed on myeloma cell lines and could be involved in the pathogenesis of bone destruction in multiple myeloma (MM). The aim of this study was to examine serum levels of HGF in untreated MM patients and its correlation with bone turnover indices and markers of disease activity. Forty-seven newly diagnosed MM patients and 25 controls were included: 12 patients were of stage I, 13 of stage II, and 22 of stage III (Durie-Salmon classification). Bone lesions were scored from 0 to 3, according to X-ray findings. Serum osteocalcin (OC), interleukin-6 (IL-6), TNF-alpha, beta(2)-microglobulin (beta(2)M), CRP, calcium, and 24-hr urine N-telopeptide cross-links of collagen breakdown (NTx) were determined. HGF levels were significantly higher at stage III compared to stages II and I (medians: 1,990.4 vs. 1,743.8 and 1,432.4 pg/mL, respectively, P < 0.05). Similarly, NTx, IL-6, TNF-alpha, CRP, beta(2)M, and calcium increased significantly with advancing stage (P < 0.01). OC was higher at stage I in comparison to stages II and III (P < 0.01). All parameters were significantly higher in patients than controls. HGF showed a strong correlation with IL-6 and TNF-alpha and less with beta(2)M, CRP, NTx, and OC. We conclude that serum HGF levels are increased in advanced stages of MM disease and extended bone lesions. HGF correlates with IL-6 and TNF-alpha, which are cytokines involved in osteoclast stimulation in MM. However, an independent association of HGF with bone turnover markers was not shown in this study, thus its role in MM bone disease needs to be further clarified.     

Plasma hepatocyte growth factor is a novel marker of AL cardiac amyloidosis

Abstract

Background: Cardiac amyloidosis is an infiltrative cardiomyopathy that is challenging to diagnose. We hypothesized that the novel biomarkers hepatocyte growth factor (HGF), galectin-3 (GAL-3), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) would be elevated in cardiac amyloidosis and may be able to discriminate from non-cardiac systemic amyloidosis or other cardiomyopathies with similar clinical or morphologic characteristics.

Methods: Patients were selected from the Vanderbilt Main Heart Registry according to the following groups: (1) amyloid light-chain (AL) cardiac amyloidosis (n?=?26); (2) transthyretin (ATTR) cardiac amyloidosis (n?=?7); (3) left ventricular hypertrophy (LVH) (n?=?45); (4) systolic heart failure (n?=?42); and (5) non-cardiac systemic amyloidosis (n?=?7). Biomarkers were measured in stored plasma samples. Biomarkers' discrimination performance in predicting AL cardiac amyloidosis (i.e., Concordance index) was reported. A survival analysis was used to explore the relationship between HGF levels and mortality among AL cardiac amyloidosis patients.

Results: HGF levels were markedly elevated in patients with AL cardiac amyloidosis (median?=?622, interquartile range (IQR): 299–1228?pg/mL) compared with the other groups, including those with non-cardiac systemic amyloidosis (median?=?134, IQR: 94–163?pg/mL, p?<?0.001). HGF was not a specific marker for ATTR amyloidosis. Gal-3 was elevated in all groups with amyloidosis but could not differentiate between those with and without cardiac involvement. There was no difference in IL-6 or VEGF between those with AL cardiac amyloidosis compared to other groups (p?=?0.13 and 0.057, respectively).

Conclusions: HGF may be a specific marker that distinguishes AL cardiac amyloidosis from other cardiomyopathies with similar clinical or morphologic characteristics. Further studies are necessary to determine whether HGF levels predict the likelihood of survival.     

Multiple myeloma cells catalyze hepatocyte growth factor (HGF) activation by secreting the serine protease HGF-activator

Multiple myeloma (MM) is a common hematologic neoplasm consisting of malignant plasma cells, which expand in the bone marrow. A potential key signal in the evolution of MM is hepatocyte growth factor (HGF), which acts as a potent paracrine and/or autocrine growth factor and survival factor for MM cells. Proteolytic conversion of HGF into its active form is a critical limiting step in HGF/MET signaling. Here, we show that malignant MM plasma cells convert HGF into its active form and secrete HGF-activator (HGFA), a serine protease specific for HGF activation. By using serine protease inhibitors and neutralizing antibodies, we demonstrate that HGFA produced by the MM cells is responsible for their ability to catalyze HGF activation. We, therefore, suggest that autocatalyzation of HGF conversion by MM cells is an important step in HGF/MET-induced myeloma growth and survival, which may have implications for the management of this incurable form of cancer.     

Activation of hepatocyte growth factor in monkey stomach following gastric mucosal injury

Background Hepatocyte growth factor (HGF) is involved in the proliferation and migration of various types of epithelial cells. HGF is produced as a single-chain precursor (pro-HGF) and functions after activation by HGF activator (HGFA). In this study, we aimed to examine the activation of pro-HGF to mature HGF and the expressions of HGF-related molecules, such as HGFA and HGFA inhibitor type 1 (HAI-1), in a monkey model of gastric mucosal injury.Methods Gastric mucosal injury was induced in Japanese monkeys by administration of HCl using nasal-gastric tubes. HGF activation was evaluated by Western blotting and enzyme-linked immunosorbent assay (ELISA), and the expression of HGF, HGFA, HAI-1, and c-Met were examined by Northern blotting and immunohistochemistry.Results Pro-HGF, but not mature HGF, was detected in normal gastric mucosa. When gastric mucosal injuries were induced, the expression of HGF significantly increased, and immunostaining of HGF was detected in fibroblasts in the gastric mucosa. In addition, conversion to mature HGF was observed in the injured gastric tissues, and mature HGF continued to increase for 48h. HGFA was stably expressed in monkey livers, regardless of HCl administration. HAI-1 expression was detected in normal gastric mucosa, and its levels decreased after the induction of gastric mucosal injury.Conclusions These results indicate that pro-HGF is stored in normal gastric tissues, and suggest that its conversion to mature HGF, associated with HGFA and HAI-1, is important for the repair of gastric mucosal injury.     

High levels of soluble syndecan-1 in myeloma-derived bone marrow: modulation of hepatocyte growth factor activity

Syndecan-1 is a heparan sulfate proteoglycan expressed on the surface of, and actively shed by, myeloma cells. Hepatocyte growth factor (HGF) is a cytokine produced by myeloma cells. Previous studies have demonstrated elevated levels of syndecan-1 and HGF in the serum of patients with myeloma, both of negative prognostic value for the disease. Here we show that the median concentrations of syndecan-1 (900 ng/mL) and HGF (6 ng/mL) in the marrow compartment of patients with myeloma are highly elevated compared with healthy controls and controls with other diseases. We show that syndecan-1 isolated from the marrow of patients with myeloma seems to exist in an intact form, with glucosaminoglycan chains. Because HGF is a heparan-sulfate binding cytokine, we examined whether it interacted with soluble syndecan-1. In supernatants from myeloma cells in culture as well as in pleural effusions from patients with myeloma, HGF existed in a complex with soluble syndecan-1. Washing myeloma cells with purified soluble syndecan-1 could effectively displace HGF from the cell surface, suggesting that soluble syndecan-1 can act as a carrier for HGF in vivo. Finally, using a sensitive HGF bioassay (interleukin-11 production from the osteosarcoma cell line Saos-2) and intact syndecan-1 isolated from the U-266 myeloma cell line, we found that the presence of high concentrations of syndecan-1 (more than 3 microg/mL) inhibited the HGF effect, whereas lower concentrations potentiated it. HGF is only one of several heparin-binding cytokines associated with myeloma. These data indicate that soluble syndecan-1 may participate in the pathology of myeloma by modulating cytokine activity within the bone marrow.     

Hepatocyte growth factor mobilizes and recruits hematopoietic progenitor cells into liver through a stem cell factor‐mediated mechanism

Aims: Although bone marrow cells are reported to migrate to the liver under circumstances of severe liver injury, the bone marrow cell type and the mechanisms in this process, remain to be clarified. We examined the involvement of hepatocyte growth factor (HGF) in this process and the cell type of migrated hematopoietic cells by HGF. Methods: The CD34⁺ cells and colony forming cells in the peripheral blood were examined in HGF transgenic, recombinant HGF‐administered, and HGF‐expressing adenovirus‐administered mice. The cell type mobilized by HGF was examined by the percentages of donor cells in the peripheral blood of the recipient mice transplanted with Lin^‐c‐kit⁺Sca‐1⁺CD34⁺ cells and those with Lin^‐c‐kit⁺Sca‐1⁺CD34^‐ cells. Expression of stem cell factor (SCF) was examined after the addition of HGF in MS‐5 stromal cells. The numbers of the cells which were mobilized from bone marrow and recruited into liver by HGF were assessed using green fluorescence fluorescent (GFP)‐chimera mice. Results: Mobilized CD34+ cells and colony forming cells in the peripheral blood were increased by HGF treatment. The cells mobilized by HGF were mostly Lin^‐c‐kit⁺Sca‐1⁺CD34⁺ cells. Recruitment of bone marrow cells into liver was not suppressed in MMP‐9‐/‐ mice. Expression of SCF was induced by HGF in MS‐5 stromal cells. However, expression of CXCR4, SDF‐1, MMP‐9 or VCAM‐1 was not changed. The numbers of GFP‐positive cells in liver 1 month after treatment by HGF was greater than that by G‐CSF. Conclusion: The results of the present study suggest that HGF mobilizes and recruits hematopoietic progenitor cells from bone marrow into the liver through SCF‐mediated mechanism.     

Relationship between bone marrow angiogenesis and plasma cell infiltration and serum β2-microglobulin levels in patients with multiple myeloma

There is growing evidence that angiogenesis is important not only in solid tumors but also in hematological malignancies. Recently, we found that bone marrow angiogenesis is a prognostic factor for disease-related survival in patients with multiple myeloma. In this report, we addressed the question of whether the microvessel density in bone marrow biopsies is correlated to other myeloma parameters, e.g., serum beta2-microglobulin (beta2-MG) and plasma cell infiltration in the bone marrow. In 22 multiple myeloma patients, immunohistochemical, CD34-stained, paraffin-embedded bone marrow biopsies before and after chemotherapy were studied. Microvessels were counted in 400x magnification, and the mean number of vessels per area in each sample was noted as the microvessel density (MVD). Pretreatment bone marrow MVD (median: 44, range: 11-175 vessels/mm2) correlated significantly with the bone marrow plasma cell infiltration (median: 30%, range: 5-90%, r = 0.642, P=0.001) and beta2-MG (median: 2.74, range: 1.4-26.1 mg/l, r = 0.749, P < 0.0005). In contrast, there was no correlation between posttreatment MVD and plasma cell infiltration or beta2-MG (median: MVD 31, range: 0-221 vessels/mm2, median plasma cell infiltration: 15%, range: 5-80%, r = 0.229, P = 0.306 and median beta2-MG: 2.65, range: 1-27.6 mg/l, r = -0.042, P = 0.853). These findings show that the strong correlations between bone marrow MVD and plasma cell infiltration as well as serum beta2-MG levels disappear after chemotherapy. The underlying mechanisms need further investigations.     

Induction of hepatocyte growth factor activator messenger RNA in the liver following tissue injury and acute inflammation

Hepatocyte growth factor activator (HGFA) is a serine protease that is responsible for localized activation of hepatocyte growth factor (HGF) in injured tissue. The activated HGF may be involved in regeneration of the injured tissue. HGFA is produced and secreted by the liver and circulates in the plasma as an inactive zymogen. In response to tissue injury, the HGFA zymogen is converted to the active form by limited proteolysis. In this study, we isolated a rat HGFA complementary DNA (cDNA) clone and analyzed the production of HGFA messenger RNA (mRNA) in response to tissue injury using this cDNA clone as a probe. The nucleotide sequence of the cDNA revealed that the amino acid sequences of rat and human HGFA showed a high degree of conservation in the regions of the characteristic domain structures, suggesting that rat and human HGFA are activated by a similar mechanism and have similar enzymatic activities in vivo. Tissue distribution analysis showed that the liver was the major site of rat HGFA mRNA synthesis. Moreover, the cells producing HGFA mRNA were identified as parenchymal liver cells. The level of HGFA mRNA increased in the liver after hepatotoxin or nephrotoxin treatment. This increase was also observed during acute inflammation induced by turpentine. These results suggest that the increase in production of HGFA mRNA in response to tissue injury is the result of an inflammatory response, and that HGFA is an acute phase protein.(Hepatology 1997 Jan;25(1):97-102)     

High serum hepatocyte growth factor level in patients with non-Hodgkin's lymphoma

Higher pretreatment serum hepatocyte growth factor (HGF) levels were observed in patients with multiple myeloma and Hodgkin's disease, but not in those with non-Hodgkin's lymphoma (NHL). We examined patients' serum levels at diagnosis using enzyme-linked immunosorbent assay and histological expression of HGF in pathological specimens of lymphoma, in relation to clinical features. The subjects were 77 NHL patients and 40 healthy controls. The serum levels of HGF in NHL patients at diagnosis were significantly higher than those in healthy controls (median 1019 vs. 689 pg/mL, P < 0.001). At diagnosis, patients with more than two sites of extranodal involvement (P = 0.001), higher scores of international prognostic index (P = 0.015), and advanced Ann Arbor stage (P = 0.023) had a higher level of serum HGF. Although the association of pretreatment serum HGF level and survival was not significant, a correlation of serial change of serum HGF levels with treatment response was found in limited cases. Furthermore, HGF expression of lymphoma tissues was shown in 18 of 24 (75%) different NHL subtypes, including most of the diffuse large B cell lymphoma (12 of 15, 80%). In conclusion, our study showed higher pretreatment serum HGF levels in NHL patients, which was related to clinical features; and the serial change of HGF seemed to parallel the treatment response. The pathogenic role of HGF in NHL patients was further highlighted by a modest expression of HGF in most of the diffuse large B cell lymphoma.     

Vitamin D deficiency does not alter biochemical markers of bone metabolism before or after autograft in patients with multiple myeloma

So far, only one study has demonstrated a high incidence of vitamin D deficiency in patients with multiple myeloma. Vitamin D deficiency may alter bone remodelling in myeloma. In this study, we aimed to determine the prevalence of vitamin D deficiency and to assess its impact on bone remodelling and bone mineral density before and after autologous stem cell transplantation (ASCT). Patients and methods: In 39 consecutive patients receiving high‐dose chemotherapy (melphalan 200 mg/m²) followed by ASCT for multiple myeloma, we measured before (T0) and 12 months after ASCT (T12) serum calcium, 25‐OH‐D, PTH 1‐84, bone alkaline phosphatase (bALP), serum C‐terminal cross‐linking telopeptide and lumbar spine bone mineral density (BMD). Results: Mean vitamin D levels were low: 15 ± 5 ng/mL (9–18) at T0 and 16 ± 5 ng/mL (14–22) at T12. Twenty‐six patients (68%) had vitamin D deficiency (25‐OH‐D < 20 ng/mL) at T0 and 58% at T12. Patients in the vitamin D‐deficient group had higher serum PTH levels than those in the vitamin D‐sufficient group : 71 ± 24 pg/mL vs. 52 ± 18 pg/mL (P = 0.04). Biochemical bone markers were identical in both groups at T0 and T12. Z‐score values did not significantly differ between the two groups at T0 and T12. There were no correlations between 25‐OH‐D and BMD or bone marker levels. Conclusion: Vitamin D deficiency does not impair biochemical markers of bone metabolism in patients with multiple myeloma, before or after ASCT.     

Serum osteoprotegerin levels are reduced in patients with multiple myeloma with lytic bone disease

Osteoprotegerin (OPG), the neutralizing decoy receptor for the osteoclast activator RANK ligand, was measured in serum taken from patients with multiple myeloma at the time of diagnosis. Median OPG was lower in the patients with myeloma (7.4 ng/mL; range, 2.6-80; n = 225) than in healthy age- and sex-matched controls (9.0 ng/mL; range 5.1-130; n = 40; P =.02). Importantly, OPG levels were associated with degree of radiographically assessed skeletal destruction (P =.01). The median OPG level in patients lacking osteolytic lesions was 9.1 ng/mL, as compared with 7.6 ng/mL and 7.0 ng/mL, respectively, in patients with minor or advanced osteolytic disease. Furthermore, OPG levels were associated with World Health Organization performance status (P =.003) and correlated to serum levels of carboxy-terminal propeptide of type I procollagen (PICP; P <.001) but not with clinical stage or survival. These findings suggest impaired OPG function in myeloma and give a rationale for OPG as a therapeutic agent against myeloma bone disease.     

Metabolism of Hepatocyte Growth Factor in the Heart in Patients with Coronary Artery Disease: Implication for Coronary Arteriosclerosis

Purpose: HGF, one of endothelium-specific growth factors, might contribute to the repair process of vascular endothelial cell damage, suggesting that serum HGF concentration may be elevated in patients with arteriosclerosis. However, the cardiac metabolism of HGF has not been examined in patients with coronary artery disease (CAD). We examined the levels of hepatocyte growth factor (HGF) in the coronary circulation and its correlation with the severity of arteriosclerosis in patients with CAD. Methods: We measured serum HGF concentration obtained from the coronary sinus (CS) and ascending aorta (AA) in patients with atherosclerotic CAD (Group E, n = 33) or vasospastic angina (Group V, n = 26), or normal control subjects (Group N, n = 12). In Group E, the severity of coronary artery stenosis was evaluated using the Gensini's score. Results: Serum HGF concentrations (ng ml) in the CS were 0.112 ± 0.008 in Group E (p < 0.001 vs. Group V, p < 0.001 vs. Group N), 0.197 ± 0.012 in Group V (p = 0.031 vs. Group N), and 0.245 ± 0.021 in Group N. Serum HGF concentrations in the AA were 0.282 ± 0.014 in Group E (p = 0.045 vs. Group V, p = 0.021 vs. Group N), 0.246 ± 0.012 in Group V, and 0.237 ± 0.009 in Group N. Serum HGF extraction in the heart (HGF in the AA-HGF in the CS) in Group E (0.170 ± 0.018) was significantly higher compared with in Group V (0.049 ± 0.011) or Group N (0.008 ± 0.005). There was a significant negative correlation between the severity of coronary arteriosclerosis and serum HGF concentration in CS (r = –0.66, p < 0.001), and a significant positive correlation between the severity of coronary arteriosclerosis and HGF extraction in the heart (r = 0.75.p < 0.001). Conclusions: We conclude that the difference of HGF levels between CS and AA in patients with CAD are decreased, and extent of decreases in HGF levels correlates with the severity of coronary arteriosclerosis. The abnormality of HGF metabolism in the heart may contribute to the progression of coronary arteriosclerosis.     

部分肝切除后的肝损伤血清和肝细胞生长因子促进大鼠骨髓细胞表达甲胎蛋白和白蛋白

目的 检测大鼠骨髓中是否存在肝脏干细胞，并用肝损伤血清和肝细胞生长因子(HGF)刺激骨髓细胞向肝细胞转化。方法 SD大鼠骨髓单个核细胞分3组进行培养：(1)单纯培养基对照组；(2)肝损伤血清组(15％，血清来自于2-AAF 75％肝切除大鼠)；(3)HGF(20ng／ml)组。用甲胎蛋白(AFP)和白蛋白作为细胞标志，用免疫组织化学、逆转录聚合酶链反应(PCR)、巢式PCR和western blot方法，观察大鼠肝损伤血清和HGF对骨髓细胞转化的促进作用。结果 肝损伤血清组和HGF组培养后10d和20d AFP免疫组织化学和western blot染色阳性；RT-PCR AFP mRNA阳性，新鲜骨髓细胞和单纯IMDM／F12培养基组AFP蛋白和mRNA均阴性。新鲜骨髓细胞存在白蛋白mRNA表达，在肝损伤血清组和HGF组培养后10d和20d，白蛋白mRNA表达增强。结论 大鼠肝损伤血清和HGF可促使体外培养骨髓细胞表达AFP mRNA和AFP。骨髓中可能存在骨髓源性肝干细胞，并微弱表达白蛋白mRNA；肝损伤血清和HGF可以促进骨髓细胞表达白蛋白mRNA。     

Serum levels of platelet-derived growth factor-BB and vascular endothelial growth factor as prognostic factors for patients with fulminant hepatic failure

Background and Aims: In animal models for acute liver injury, the administration of some angiogenic factors such as vascular endothelial growth factor (VEGF) and granulocyte‐colony stimulating factor (G‐CSF) are shown to reduce liver injury and improve liver proliferative capacity. The aim of the present study was to assess the role of angiogenic factors in fulminant hepatic failure (FHF). Methods: Serum levels of nine angiogenic factors (angiopoietin‐2, follistatin, G‐CSF, hepatocyte growth factor [HGF], interleukin‐8, leptin, platelet‐derived growth factor [PDGF]‐BB, platelet endothelial cell adhesion molecule‐1 and VEGF) were measured using the Bio‐Plex Protein Array System in 30 patients, 17 of whom were diagnosed with FHF, 13 with acute hepatitis (AH), and 20 controls. Results: Serum levels of PDGF‐BB and VEGF were lower in FHF patients than AH patients and controls (PDGF‐BB; 2050 ± 1572 pg/mL vs 4521 ± 2419 pg/mL vs 8506 ± 5500 pg/mL, VEGF; 39 ± 38 pg/mL vs 144 ± 122 pg/mL vs 205 ± 121 pg/mL). By using univariate logistic regression models, serum levels of PDGF‐BB and VEGF were associated with poor outcomes. Serum PDGF‐BB levels were strongly correlated with serum VEGF levels (r = 0.70). Furthermore, serum PDGF‐BB levels were significantly correlated with platelet counts (r = 0.79), PT activity (r = 0.37) and D.Bil/T.Bil ratio (r = 0.50), while serum VEGF levels were significantly correlated with platelet counts (r = 0.68) and PT activity (r = 0.38). Conclusions: We consider that serum levels of PDGF‐BB and VEGF are worth investigating as biomarkers for predicting outcomes of FHF patients.