HGF Plasma Levels Research Articles

Peripheral inflammatory response in people after acute ischaemic stroke and isolated spontaneous cervical artery dissection.

The systemic inflammatory response following acute ischaemic stroke remains incompletely understood. We characterised the circulating inflammatory profile in 173 acute ischaemic stroke patients by measuring 65 cytokines and chemokines in plasma. Participants were grouped based on their inflammatory response, determined by high-sensitivity C-reactive protein levels in the acute phase. We compared stroke patients' profiles with 42 people experiencing spontaneous cervical artery dissection without stroke. Furthermore, variations in cytokine levels among stroke aetiologies were analysed. Follow-up samples were collected in a subgroup of ischaemic stroke patients at three and twelve months. Ischaemic stroke patients had elevated plasma levels of HGF and SDF-1α, and lower IL-4 levels, compared to spontaneous cervical artery dissection patients without stroke. Aetiology-subgroup analysis revealed reduced levels of nine cytokines/chemokines (HGF, SDF-1α, IL-2R, CD30, TNF-RII, IL-16, MIF, APRIL, SCF), and elevated levels of IL-4 and MIP-1β, in spontaneous cervical artery dissection (with or without ischaemic stroke as levels were comparable between both groups) compared to other aetiologies. The majority of cytokine/chemokine levels remained stable across the study period. Our research indicates that stroke due to large artery atherosclerosis, cardioembolism, and small vessel occlusion triggers a stronger inflammatory response than spontaneous cervical artery dissection.

Plasma HGF concentration in patients with brain tumors.

The Hepatocyte Growth Factor is a strong mitogenic factor and seems to play important role in tumor angiogenesis. The purpose of this study was to analyse the plasma concentration of this factor in patients treated surgically because of intracranial tumors. The study included 47 patients, both sexes treated surgically for intracranial tumors and 30 adult volunteers of both sexes, without cancer diagnosis. In study group 4 measurements of plasma HGF were taken: measurement 1: within 24 hours to 1 hour before the operation (preoperative), measurement 2: on the first day after the operation, i.e. after 24 hours, measurement 3: between the third and fifth day following the treatment, i.e. within 72–120 hours, and measurement 4: on the seventh day after the operation, i.e. after 840 hours. In control group only one measurement was taken. The distribution of the analyzed parameters was different from the normal distribution, therefore nonparametric statistics were used. The result values are presented in the form of a median (Me). The analysis revealed that HGR plasma levels in the patients with intracranial tumors in all 4 measurements (Me1 = 543.16 pg/ml, Me2 = 762.59 pg/ml, Me3 = 819.82 pg/ml, Me4 = 804.82 pg/ml) in the perioperative period were elevated in comparison to healthy subjects (Me = 361.04 pg/ml). The association has been shown to exist between postoperative HGF plasma levels and the clinical condition of patients with intracranial tumors (p = 0.0342). Postoperative HGF levels correlated negatively with the patients' postoperative condition. It was also found that in patients with supratentorial tumors HGF plasma levels were higher (Me = 557.74 pg/ml) in comparison to patients with posterior fossa tumors (Me = 325.00 pg/ml). These results suggest increased angiogenic and mitogenic activity in patients with intracranial tumors and its even greater intensity in the postoperative period. Greater angiogenic activity appears to occur in patients with supratentorial tumors.

Hepatocyte growth factor plays a particular role in progression of overall cardiac damage in experimental pulmonary hypertension.

Background: HGF/MET pathway may have a role in pulmonary hypertension (PH). However, the link between the pathway and development of target organ damage in PH remains elusive. We aimed to demonstrate the relation between plasma HGF and HGF/MET tissue expressions in affected organs during PH progression.Methods: 12 weeks old male Wistar rats were injected with monocrotaline (MCT, 60 mg/kg, s.c.) to induce PH and sacrificed after 1, 2 and 4 weeks. Controls received saline. mRNA levels of HGF regulatory complex (Hgf, Met, Hgfa, Hai-1, Hai-2) were determined in right and left ventricles (RV, LV), lungs, pulmonary artery and liver by RT-qPCR. HGF protein levels in plasma were analysed by ELISA.Results: PH development was associated with a progressive elevation of HGF plasma levels that correlated with relative RV mass. Furthermore, Hgf mRNA expressions at week 4 were upregulated solely in the cardiac ventricles while being downregulated in a. pulmonalis, lungs and liver. Met and Hai-1/Hai-2 followed a similar pattern and were upregulated in cardiac ventricles, where Hgfa remained unchanged, but downregulated in lungs.Conclusion: We suggest that cardiac overexpression of Hgf might contribute to increased plasma HGF in MCT-induced PH. HGF could be exploited as a cardiospecific biomarker and HGF/MET pathway as a target in drug discovery for PH.

Effect of alcohol on the interleukin 6-mediated inflammatory response in a new mouse model of acute-on-chronic liver injury

Background and AimsACLF is usually associated with a precipitant in the setting of a chronically damaged liver. We aim to combine a mouse model with a pre-injured liver (Abcb4/Mdr2−/−) with a recently standardized ethanol feeding model to dissect alcohol-related inflammatory responses in this model. MethodTen (n = 64) and 15 (n = 64) week old wild-type (WT) C57BL/6 J and Abcb4−/− knock-out (KO) mice were either fed control (WT/Cont and KO/Cont groups) or liquid ethanol diet (5% v/v) followed by an ethanol binge (4 mg/kg) (WT/EtOH and KO/EtOH groups). Hepatic mRNA levels of IL6, IFN-G, IL-1B, TGFB1, TNF-A, CCL2, HGF, CRP, RANTES, PNPLA3 and COL3A1 were evaluated using the 2−ΔΔCt method. IL6 and HGF plasma levels were quantified by ELISA. ResultsOlder mice in KO/EtOH group displayed higher IL6 expressions compared to KO/Cont, WT/EtOH and WT/Cont groups of the same age, whereas HGF did not differ. Significant over-expression of CCL2 also corresponded to the same group. Males in KO/EtOH group exhibited higher IL6 expression than females. Lipid droplets were observed in about 80% of mice challenged with ethanol. There was a profound downregulation in PNPLA3 and RANTES levels after ethanol exposure. Mean size of the LDs was inversely correlated with hepatic PNPLA3 levels. ConclusionWe propose a novel promising approach to model alcohol-related ACLI. Acute inflammatory IL6-driven response might help transition from a stable chronic state to a progressive liver damage in Abcb4−/− mice. Repression of PNPLA3 resulted in a notable expansion in size of lipid droplets, indicating lipid remodeling in this model.

Identification of core active disaccharides in heparin for HGF-inducing activity.

Objectives:To ascertain the positions of sulfated groups for HGF-inducing activity using differently sulfated heparin disaccharides and to investigate whether the heparin disaccharide elevates HGF levels in plasma in vivo and exerts protective effects on acute liver injury.Materials and Methods:The heparin disaccharides ΔUA-GlcNS, ΔUA (2S)-GlcN, ΔUA-GlcNAc (6S), ΔUA-GlcNS (6S), ΔUA (2S)-GlcNS, ΔUA (2S)-GlcNAc (6S), ΔUA-GlcNAc and ΔUA (2S)-GlcNS (6S) were added to MRC-9 fibroblasts and HGF concentrations in culture media were determined by enzyme-linked immunosorbent assay. Furthermore, ΔUA-GlcNS (100 μg/head) was injected into C57BL/6 mice and plasma levels of HGF measured at 12 h. After acute hepatitis was induced by CCl4 (15 mg/kg) in mice, liver specimens were stained with hematoxylin and eosin (H and E). Levels of aspartate aminotransferase and alanine aminotransferase were measured at 24 h.Results:Among the disaccharides investigated, ΔUA-GlcNS, ΔUA-GlcNAc (6S) and ΔUA-GlcNS (6S) stimulated HGF production in MRC-9 fibroblasts. However, none of the 2-O-sulfated disaccharides [ΔUA (2S)-GlcNS, ΔUA (2S)-GlcNAc (6S) and ΔUA (2S)-GlcNS (6S)] showed any activity despite the presence of N-sulfated and/or 6-O-sulfated disaccharides. Thus, 2-O-sulfation of hexuronic acid has an inhibitory effect. Moreover, ΔUA-GlcNS administration increased plasma levels of HGF in normal mice and prevented CCl4-induced liver injury in mice.Conclusions:N-sulfation and/or 6-O-sulfation of glucosamine with nonsulfated hexuronic acid provides a structural basis for the HGF-inducing activity of disaccharides. ΔUA-GlcNS increases plasma levels of HGF and protects against CCl4-induced acute liver injury.

Pubertal high fat diet: effects on mammary cancer development

IntroductionEpidemiological studies linking dietary fat intake and obesity to breast cancer risk have produced inconsistent results. This may be due to the difficulty of dissociating fat intake from obesity, and/or the lack of defined periods of exposure in these studies. The pubertal mammary gland is highly sensitive to cancer-causing agents. We assessed how high fat diet (HFD) affects inflammation, proliferative, and developmental events in the pubertal gland, since dysregulation of these can promote mammary tumorigenesis. To test the effect of HFD initiated during puberty on tumorigenesis, we utilized BALB/c mice, for which HFD neither induces obesity nor metabolic syndrome, allowing dissociation of HFD effects from other conditions associated with HFD.MethodsPubertal BALB/c mice were fed a low fat diet (12% kcal fat) or a HFD (60% kcal fat), and subjected to carcinogen 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis.ResultsHFD elevated mammary gland expression of inflammatory and growth factor genes at 3 and 4 weeks of diet. Receptor activator of nuclear factor kappa-B ligand (RANKL), robustly induced at 4 weeks, has direct mitogenic activity in mammary epithelial cells and, as a potent inducer of NF-κB activity, may induce inflammatory genes. Three weeks of HFD induced a transient influx of eosinophils into the mammary gland, consistent with elevated inflammatory factors. At 10 weeks, prior to the appearance of palpable tumors, there were increased numbers of abnormal mammary epithelial lesions, enhanced cellular proliferation, increased growth factors, chemokines associated with immune-suppressive regulatory T cells, increased vascularization, and elevated M2 macrophages. HFD dramatically reduced tumor latency. Early developing tumors were more proliferative and were associated with increased levels of tumor-related growth factors, including increased plasma levels of HGF in tumor-bearing animals. Early HFD tumors also had increased vascularization, and more intra-tumor and stromal M2 macrophages.ConclusionsTaken together in this non-obesogenic context, HFD promotion of inflammatory processes, as well as local and systemically increased growth factor expression, are likely responsible for the enhanced tumorigenesis. It is noteworthy that although DMBA mutagenesis is virtually random in its targeting of genes in tumorigenesis, the short latency tumors arising in animals on HFD showed a unique gene expression profile, highlighting the potent overarching influence of HFD.

Determination of the maximum tolerated dose (MTD) of MGCD265, an oral Met/VEGFR multitargeted receptor tyrosine kinase inhibitor, in combination with docetaxel.

3032 Background: MGCD265 targets wild type Met, as well as clinically relevant Met mutants, VEGFR-1,-2 and -3, Ron and Tie-2. MGCD265 combinability with docetaxel has been evaluated in patients (pts) with advanced malignancies. Methods: In the first portion of this phase I/II study, the primary objective was to determine the safety profile of the combination including the MTD and the dose liming toxicities (DLTs). Secondary objectives include anti-tumor activity, pharmacodynamics (PD) and pharmacokinetics (PK). Incremental MGCD265 dose increases of 50% occurred in cohorts of 3-4 pts in the absence of a DLT. If a DLT was observed during the first cycle of treatment, a minimum of 6 safety evaluable pts were enrolled at that dose level. Daily (QD) and twice daily (BID) dosing of MGCD265 were evaluated. Docetaxel was administered intravenously on Day 1 of each 21-day cycle. Results: Pt characteristics (n=23): gender: 13 M/10 F; median age: 69 (range 52-78) years; ECOG 0/1: 12/11. The MTD was determined to be MGCD265 72 mg/m2 BID + docetaxel 75 mg/m2. The observed DLTs were grade 3 diarrhea (n=1), grade 3 fatigue (n=1) and grade 3 lipase elevation (n=2). Grade 2 and above treatment-related adverse events in ≥ 3 pts include anorexia, diarrhea, fatigue and neutropenia. Eight pts with NSCLC have been recruited: 2 pts experienced a partial response (one pt for ~ 8 cycles and one pt after 2 cycles and continuing) and 3 pts experienced prolonged disease stabilization (12, 14 and 18 cycles). Four of these 5 pts had previous taxane therapy for their NSCLC. The available archived tumor biopsy from 3 of these pts showed Met and phospho-Met protein expression. At Cycle 1 Day 8, a decrease in plasma levels of HGF and an increase in plasma levels of VEGF were noted. Preliminary PK data with MGCD265 in QD dosing indicated no drug-drug interaction and MGCD265 steady state plasma concentrations were multiples above the IC50 for Met and VEGFR2. Conclusions: MGCD265 can be safely combined with docetaxel with early signs of clinical activity. The MTD was determined to be MGCD265 72 mg/m2 BID + docetaxel 75 mg/m2. This combination merits additional testing in second-line NSCLC patients.

MGCD265, an oral Met/VEGFR multitargeted receptor tyrosine kinase inhibitor, in combination with erlotinib: Phase I clinical experience.

3083 Background: MGCD265 targets wild type Met, as well as clinically relevant Met mutants, VEGFR-1,-2 and -3, Ron and Tie-2. MGCD265 combinability with erlotinib is being evaluated in patients (pts) with advanced malignancies. Combining Met and EGFR inhibitors has recently been shown to be synergistic and can overcome resistance to either Met or EGFR inhibitors. Methods: Eligible pts in the initial cohort received MGCD265 at 96 mg/m2 once daily (QD) and erlotinib at 100 mg QD. Subsequent cohorts received full dose erlotinib (150 mg QD) with incremental doses of MGCD265, initially on a QD schedule and thereafter twice daily (BID) during a 21-day cycle. The primary objective was to determine the safety profile. Secondary objectives include anti-tumor activity, pharmacodynamics (PD) and pharmacokinetics (PK). Results: Pt characteristics (n=33): gender: 23 M/10 F; median age: 57 (range 39-76) years; ECOG 0/1: 18/15. Dose limiting toxicities include: diarrhea (1/8 pts at MGCD265 96 mg/m2 QD + erlotinib 100 mg); rash (1/9 pts at MGCD265 144 mg/m2 QD + erlotinib 150 mg) and fatigue (1/9 pts at MGCD265 144 mg/m2 QD + erlotinib 150 mg). The BID regimen of MGCD265 has been introduced at 72 mg/m2. One pt with NSCLC experienced a partial response (after 2 cycles of treatment and continuing) and one pt with gastric cancer had resolution of ascites and a decrease in gastric wall thickness (cycle 15 and continuing). Molecular profiling of the archived tumor biopsy from this latter pt showed high levels of Met and phospho-Met protein expression in the absence of MET and EGFR gene amplification or detectable mutations. Prolonged disease stabilization was observed in another pt with gastric cancer (8 cycles and continuing). Ten other pts completed 4-10 cycles. To date, a decrease in HGF plasma levels was observed in Cycle 1 Day 8. Preliminary PK data with MGCD265 in QD dosing indicated no drug-drug interaction and MGCD265 steady state plasma concentrations were multiples above the IC50 for Met and VEGFR2. Conclusions: Clinical data to date indicate that MGCD265 can be combined with full dose erlotinib with early signs of clinical activity. This combination merits additional testing in NSCLC and gastric cancer.

Predictive Value of Plasma Hepatocyte Growth Factor/Scatter Factor Levels in Patients with Clinically Localized Prostate Cancer

Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional cytokine that is involved in cancer growth, motility, invasion, and angiogenesis. We assessed whether preoperative plasma levels of HGF can enhance the accuracy of standard models for predicting pathologic features and clinical outcomes. The study comprised 421 consecutive patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostatic adenocarcinoma. HGF/SF was measured using a commercially available immunoassay. Multivariate logistic regression was used to assess the relationship between plasma HGF/SF and pathologic features. Multivariate Cox regression was used to predict disease recurrence. One thousand bootstrap replicates were created for internal validation and predictive accuracies were estimated for each model. Plasma HGF/SF levels were significantly elevated in patients with lymph node and/or seminal vesicle invasion (P < 0.0001 and P = 0.007, respectively). Preoperative plasma HGF/SF level was an independent predictor of lymph node invasion [odds ratio (OR) for every 100 pg/mL increase in HGF/SF, 1.82; 95% confidence interval (95% CI), 1.33-2.49] and seminal vesicle invasion (OR, 1.18; 95% CI, 1.06-1.3). Addition of HGF/SF increased the accuracy of a base model that included standard preoperative variables for prediction of lymph node invasion by 6.7% (predictive accuracy, 98.4%). HGF/SF also independently predicted disease recurrence after surgery (hazard ratio, 1.07; 95% CI, 1.0-1.15). Preoperative plasma level of HGF/SF is an independent predictor of prostate cancer metastasis to lymph nodes and disease recurrence after surgery. Use of HGF may help in therapeutic decision-making and enrollment into clinical trials.

Stem cell activation sustains hereditary hypertrophy in hamster cardiomyopathy

Recent studies have documented the presence of stem cells within the myocardium and their role in the repair of ischaemic injury. Nevertheless, the pathogenic role of stem cells in non-ischaemic myocardial diseases, as well as the factors potentially responsible for their activation, is still under debate. The present study demonstrates the presence of an increased number of c-kit positive, MDR-positive, and Sca-1-positive stem cells within the myocardium of hereditary delta-SG null hamsters, a spontaneously occurring model of hypertrophic cardiomyopathy. When hamsters are 80 days old, ie at the 'hypertrophic' stage of the disease, but without haemodynamic overload, these cells associate with a multitude of cells co-expressing c-kit, cMet, GATA4, or MEF-2, and proliferating myocytes co-expressing myosin heavy chain, telomerase, ki67 and cyclin B. Furthermore, at the same animal age, the number of myocardial cells co-expressing c-kit and Flk-1, and the number of capillary vessels, is also amplified. In order to identify factors potentially responsible for stem cell activation, the myocardial expression of HGF and cMet and HGF plasma levels were evaluated, demonstrating their increase in 80-day-old delta-SG null hamsters. To demonstrate the possible ability of HGF to induce stem cell differentiation, bone-marrow-derived mesenchymal stem cells were challenged with HGF at the same plasma concentration observed in vivo. HGF induced cMet phosphorylation, and caused loss of stem cell features and overexpression of MEF-2, TEF1, and MHC. Our results demonstrate that stem cell activation occurs within the cardiomyopathic myocardium, very likely to maintain an efficient cardiac architecture. In this context, elevated levels of HGF might play a role in induction of stem cell commitment to the cardiomyocyte lineage and in cardioprotection through its anti-apoptotic action. Consistently, when cytokine levels declined to physiological concentrations, as in 150-day-old cardiomyopathic animals, myocardial apoptosis prevailed, prejudicing cardiac function.

Intermittent and short daily hemodialysis increase HGF plasma levels and diminish HCV viral load

Decrease of HCV viral load and HGF plasma levels increase have been related to HD sessions. Beneficial effects of HGF stimulation in HD on the outcome of HCV liver disease have been described. Aim was to analyze potential differences between intermittent (3 × week) and short daily (6 × week) HD, examining differences between HCV+ and – pts. We studied 41 pts from 2 HD centres, 26 on intermittent HD (6 on line HF), 8 HCV+, and 15 on short‐daily HD with 4 HCV+ 40 pts used synthetic HD membranes (low‐flux and high‐flux). Among HCV + we determined viral load by Amplicor (Roche) pre‐ and post‐ HD. All pts were studied for HGF levels (ELISA) baseline, 15 min, end, and at start of the following session viral load is significantly higher preHD and decreases over session. High‐flux membranes were more efficient in reducing viremia (67% vs 45%), which level was higher pre‐ and post‐HD principally in patients using low‐flux membranes. Viremia in DHD is lower than in intermittent (470067.3 ± 663974.5 vs 1015695.5 ± 1202679.0). HCV+ HCV− p HGF baseline 3261.3 ± 1904.5 2186.5 ± 815.7 0.01 HGF 15 min 8000.0 ± 0.0 7774.0 ± 1129.8 ns HGF end 6142.5 ± 2262.3 4443.7 ± 2515.7 0.03 HGF start 3391.0 ± 1680.6 2311.7 ± 633.6 0.007 HGF at baseline, at the end of the session, and starting the following one was significantly higher in HCV + patients. Maximum increase appears always at 15 min. HGF levels were significantly higher in daily HD than intermittent. Of the 14 patients who showed HGF after session higher than 8000, 8 were HCV+(3 in DHD, 5 high flux), 6 were HCV−(5 DHD and 3 high flux), 14 pts finished HD session with HGF&gt;8000, 8HCV+(3 DHD, 5 high flux) and 6HCV−(5 DHD, 4 high‐flux). HGF stimulation appears in daily and intermittent HD, with higher level in the latter; HCV+ showed higher HGF vs negative, independently from the HD frequency; HCV viral load diminishes in all HD sessions, more in those with high‐flux membranes. Short‐daily HD with high‐flux synthetic membranes seems the best option for HCV+ patients, and when performed in home precludes nosocomial transmission.