- Open Access
Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety
© Ido et al; licensee BioMed Central Ltd. 2011
- Received: 1 February 2011
- Accepted: 8 May 2011
- Published: 8 May 2011
Hepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an anti-apoptotic factor. Therefore, HGF is a potential therapeutic agent for treatment of fatal liver diseases. We performed a translational medicine protocol with recombinant human HGF (rh-HGF), including a phase I/II study of patients with fulminant hepatitis (FH) or late-onset hepatic failure (LOHF), in order to examine the safety, pharmacokinetics, and clinical efficacy of this molecule.
Potential adverse effects identified through preclinical safety tests with rh-HGF include a decrease in blood pressure (BP) and an increase in urinary excretion of albumin. Therefore, we further investigated the effect of rh-HGF on circulatory status and renal toxicity in preclinical animal studies. In a clinical trial, 20 patients with FH or LOHF were evaluated for participation in this clinical trial, and four patients were enrolled. Subjects received rh-HGF (0.6 mg/m2/day) intravenously for 12 to 14 days.
We established an infusion method to avoid rapid BP reduction in miniature swine, and confirmed reversibility of renal toxicity in rats. Although administration of rh-HGF moderately decreased BP in the participating subjects, this BP reduction did not require cessation of rh-HGF or any vasopressor therapy; BP returned to resting levels after the completion of rh-HGF infusion. Repeated doses of rh-HGF did not induce renal toxicity, and severe adverse events were not observed. Two patients survived, however, there was no evidence that rh-HGF was effective for the treatment of FH or LOHF.
Intravenous rh-HGF at a dose of 0.6 mg/m2 was well tolerated in patients with FH or LOHF; therefore, it is desirable to conduct further investigations to determine the efficacy of rh-HGF at an increased dose.
- Hepatocyte Growth Factor
- Hepatic Encephalopathy
- Liver Regeneration
- Fulminant Hepatitis
- Hepatic Progenitor Cell
Acute liver failure (ALF) is a rare but fatal clinical syndrome marked by the abrupt loss of hepatic cellular function, with the subsequent development of coagulopathy, jaundice and encephalopathy [1–3]. In Japan, ALF with the histological appearance of hepatitis, caused by viral infection, autoimmune hepatitis and drug allergy-induced liver injury, is classified as fulminant hepatitis (FH) or as the related disease late-onset hepatic failure (LOHF) . FH is identified as hepatitis in which hepatic encephalopathy develops within 8 weeks after the onset of disease symptoms, with prothrombin time (PT) less than 40% of the standardized values. Also, FH is further classified into two subtypes: acute (FHA) and subacute type (FHSA) in which the encephalopathy occurs, respectively, within 10 days or after 11 days or more. Patients in whom the encephalopathy develops between 8 and 24 weeks after disease onset with PT less than 40% are diagnosed as having LOHF. This distinction is useful in guiding prognosis: the time to onset of encephalopathy is negatively correlated with outcome. The only effective therapy for FH is liver transplantation. Other therapies, including corticosteroids, have no demonstrable benefit , lamivudine for acute hepatitis B , and plasmapheresis . Therefore, patients with FH who did not receive liver transplantation had extremely poor prognoses: the survival rates were 53.7% in FHA and 24.4% in FHSA, and 11.5% in LOHF in Japan .
Hepatocyte growth factor (HGF) was first purified as a potent mitogen for hepatocytes from the plasma of patients with FH [8, 9]. HGF is one of the primary agents promoting the proliferation of mature hepatocytes [10–12]. The stimulatory effect of HGF on liver regeneration has been observed in vivo using normal and partially hepatectomized rats . Additionally, HGF stimulates proliferation of hepatic progenitor cells, which appear following hepatic injury . Furthermore, recent investigations using mice deficient in c-met, a specific receptor for HGF, demonstrated that the HGF/c-met signaling pathway is essential for efficient liver regeneration and repair [14, 15]. Conversely, HGF exerts protective and anti-apoptotic functions toward hepatocytes in vitro [16–18] and in vivo [19–21], and is able to prevent Fas (CD95/APO-1)-triggered death of adult hepatocytes, leading to rescue from Fas-induced fulminant hepatic failure . These results indicate that HGF has the potential to be a new therapeutic agent for ALF through its mitogenic and anti-apoptotic activities.
We have worked to develop translational medicine protocols for recombinant human HGF (rh-HGF), and have performed an investigator-initiated International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)-Good Clinical Practice (GCP)-registered phase I/II clinical trial of rh-HGF. As this application is the first clinical trial to administer rh-HGF to humans, we performed additional preclinical studies to ensure minimization of the predicted side effects, and then treated four patients with repeated doses of rh-HGF in order to evaluate the safety, pharmacokinetics and clinical efficacy of FH therapy.
Animal experiments to ensure safety of rh-HGF administration
Female Crown miniature swine, six to seven months of age, and male Wistar rats, seven weeks of age, were obtained from Japan Farm (Kagoshima, Japan) and Charles River Laboratories Japan Inc. (Yokohama, Japan), respectively. The animals were maintained under constant room temperature (25°C), and given free access to water and the indicated diet throughout the study. The protocol for animal studies was approved by the ethics committee of the Graduate School of Medicine, Kyoto University (Kyoto, Japan). All animal experiments were performed after one to three weeks acclimation on a standard diet.
General pharmacological test
After Female Crown miniature swine were anesthetized by inhalation of sevoflurane, nitric dioxide and oxygen, catheters were inserted into one internal jugular vein (for injection of rh-HGF) and to one common carotid artery (to measure BP). One mg/kg of rh-HGF was injected through the internal jugular vein over the course of 20 min. HR was recorded by electrocardiographic monitoring, and cardiac function was measured via echocardiography. To evaluate the effect of stepwise infusion of rh-HGF on BP, 0.4 mg/kg of rh-HGF was injected over the course of three hours, with a stepwise increase in dose rate (10% of the total dose over the first 60 min, 30% over the next 60 min, and 60% over the last 60 min) through the catheter inserted into an internal jugular vein.
Evaluation of renal toxicity of repeat dose of rh-HGF
rh-HGF (0.4, 1.0 and 4.0 mg/kg) was administered to rats intravenously in a bolus for 14 days, followed by observation for 2 weeks. Urinary excretion of albumin and protein were measured periodically during and after rh-HGF administration. Animals were sacrificed at the ends of rh-HGF administration (day 14) and the observation period (day 28) to evaluate renal involvement, including serum creatinine and histological findings.
A phase I/II clinical trial for patients with acute liver failure
This single-arm, open-labeled, and dose-escalation study was conducted at Kyoto University Hospital, Kyoto, Japan. Study protocols were reviewed and approved by the Investigational Review Board and Ethics Committee governing Kyoto University Hospital before the commencement of patient enrollment. Studies were performed in accordance with principles of GCP, and conformed to ethical guidelines of the Declaration of Helsinki. All participating patients, or (when participants were not able to subscribe because of hepatic encephalopathy) their legal representatives provided written informed consent before being enrolled into the study.
Selection of patients
Consenting patients were prospectively screened from September 2005 to June 2008. Eligible patients with FHSA or LOHF, who were not able to receive liver transplantation, met at least one of the following four parameters: (1) aged 45-year-old or above, (1) PT 10% or less of the standardized values, (3) total bilirubin (T-Bil) level of 18.0 mg/dL or more, or (4) direct/total bilirubin ratio less than 0.67. The following patients were not eligible: those under 16 years old; those treated with glucagon and insulin, or prostaglandin E1 48 hours before registration; those with presence or past-history of malignant tumors; those with heart failure; those with severe complication including pneumonia, sepsis, disseminated intravascular coagulation syndrome or gastrointestinal bleeding; and those with allergic reaction against rh-HGF. Pregnancy-aged women were also ineligible, because toxicity of rh-HGF to reproductive development in female animals has not been examined. Additionally, patients were also excluded on the grounds of renal involvement, including urinary excretion of ≥1 mg/mL protein, deformed red blood cells or RBC casts in sedimentary urine, a serum creatinine level of 2.0 mg/dL or more, or urine volume less than 400 mL/day.
Protocol therapy and observation after rh-HGF dosing period
rh-HGF was prepared as a GMP-grade material. The initial dose of rh-HGF was fixed at 0.6 mg/m2/day, which ensured not only safety but also clinical efficacy, as determined by several preclinical animal studies. In this dose escalation study, dose of rh-HGF can be increased from the initial dose (0.6 mg/m2) to 1.2, 1.8 or 2.4 mg/m2. rh-HGF was administered intravenously with a stepwise increase during 3 hours for up to 14 days, followed by a 14-day observation period. All patients were followed in order to determine the outcomes after the study period (up to 28 days).
The primary endpoint of interest was the safety of repeated doses of intravenous rh-HGF, which was evaluated on the basis of the occurrence, frequency, and severity of adverse events. All patients were treated in an intensive care unit. During the on-study period, patients were monitored for safety at regular intervals from the start of rh-HGF administration until 14 days after completion of study drug dosing. Safety assessments included physical examination, clinical laboratory test and adverse events. Adverse events were monitored throughout the duration of the study, and evaluated in terms of adverse events graded according to the Common Toxicity Criteria grading system. Causal association of adverse events with rh-HGF was determined by clinician's best judgment. All adverse events were treated appropriately regardless of the cause; where necessary, patients were withdrawn from the study. The incidence of adverse events was computed from the number of patients experiencing at least one adverse event from among those who received at least a single dose of rh-HGF.
The secondary endpoints were the pharmacokinetics of intravenously injected rh-HGF and clinical efficacy, including survival period and outcome. To examine pharmacokinetics of rh-HGF, blood samples were collected for analysis of rh-HGF at multiple time points on days 1, 3, 5, 8, and 11 for assessment. Serum concentrations of HGF were determined by enzyme-linked immunosorbent assay (ELISA) (Otsuka Co., Ltd., Tokushima, Japan) . Laboratory data, including PT-international normalized ratio (PT-INR), T-Bil, serum albumin, alanine aminotransferase (ALT), and α-fetoprotein (AFP), were examined before plasma exchange or rh-HGF administration.
To evaluate survival benefits by administration of rh-HGF, the stratified proportional hazards model was used for analyzing matched datasets. All statistical analyses were done using SAS version 9.1 (SAS Institute, Inc., Cary, NC).
Establishment of rh-HGF dosing method to respond to a decrease in blood pressure in miniature swine
Next, we tried to develop a method for rh-HGF administration that would avoid rapid BP reduction. We finally established a stepwise infusion method in which rh-HGF was administered with a stepwise increase over the course of three hours (10% dose for 60 min, 30% for next 60 min, and 60% for the last 60 min) (Figure 1B). We found that appropriate infusion effectively prevented the decrease in BP caused by intravenous rh-HGF administration (Figure 1C). The preventive effect of additional infusion also supports the idea that dilatation of capacitance vessels is a cause of HGF-induced BP reduction.
Evaluation of renal toxicity induced by repeated dose of rh-HGF in rats
Reason for not receiving LT
Before rh-HGF administration
Grade of HE
Prothrombin time INR (%)
Direct/total bilirubin ratio
Serum HGF (ng/mL)
Liver volume (mL)
Days between HE and rh-HGF administration (days)
Duration of rh-HGF dosing (days)
during the study period
during the follow-up period
Pharmacokinetics of stepwise infusion of rh-HGF for three hours
Pharmacokinetic parameters of rh-HGF
95% confidence interval
Intravenous rh-HGF was well tolerated in all patients with FH or LOHF
All patients showed slight to mild increase in urinary excretion of albumin at enrollment and a decrease in urine volume during the rh-HGF study period. However, repeated doses of rh-HGF did not increase urinary excretion of albumin, and urine volume was affected by several factors other than rh-HGF administration, including volume of infusion, amount of circulating plasma, and diuretic dosing. Although hypokalemia, anemia, a decrease in platelet count, prolonged PT, a decrease in anti-thrombin III, and hematuria were also observed in three of four patients, there was no apparent evidence for a causal relationship between these adverse events and rh-HGF administration. Patient 3, who died of advanced hepatic failure during the observation period, exhibited respiratory failure. However, this severe adverse event was associated with progression of hepatic failure, not rh-HGF; no other severe adverse events directly caused by single or repeated doses of rh-HGF were observed during the study period.
HGF administration did not show a beneficial effect on hepatic encephalopathy, laboratory data results, or patient survival
Three out of four patients exhibited hepatic encephalopathy at enrollment (Table 1). Patient 1 presented with grade II hepatic encephalopathy at the beginning of protocol therapy. This patient did not recover from hepatic encephalopathy either during or after the study period. The patient ultimately died 68 days after the onset of hepatic encephalopathy (Additional file 1). In patient 2, who had FHSA and ultimately survived, plasma exchange was performed on days 2, 4, and 8 during the HGF dosing period (Additional file 2), and hepatic encephalopathy had improved by day 3. Patient 3 showed advanced hepatic encephalopathy at enrollment. Although the consciousness level was transiently alleviated during the rh-HGF dosing period, hepatic encephalopathy continued to progress during the observation period; the patient died 28 days after the onset of hepatic encephalopathy (Additional file 3). Patient 4 had already recovered from hepatic encephalopathy at enrollment, and did not show any impairment of consciousness level during the study period (Additional file 4). Consequently, we did not observe a definite effect of rh-HGF administration on hepatic encephalopathy.
Effect of rh-HGF administration on survival time
Survival time from:
onset of hepatic encephalopathy
onset of disease
This clinical trial covered patients with FH, an extremely severe and fatal liver disease: subjects enrolled in this trial are predicted to die without liver transplantation. Indeed, a nationwide survey of the patients with FH or LOHF (1998-2002) in Japan revealed that the survival rate of the patients (n = 192) who met this study's inclusion criteria was 17.7% (n = 34). Additionally, FH is a relatively rare syndrome in Japan (698 patients between 1998 and 2003) ; patients with severe complications, especially renal dysfunction and heart failure, were excluded in order to more precisely evaluate the safety and efficacy of the proposed therapy. Therefore, we had difficulty with recruitment of trial subjects. Ultimately, we recruited only four patients to our institute, Kyoto University Hospital, for treatment with the initial dose of rh-HGF.
Predicted adverse events included a decrease in BP, by dilatation of capacitance vessels, and proteinuria. Therefore, we established a stepwise infusion method to avoid a rapid reduction of BP, and confirmed reversibility of renal toxicity through additional preclinical studies. In this clinical trial, rh-HGF was administered intravenously for 12 to 14 days, and severe side effects and complications caused by rh-HGF dosing were not observed. BP was gradually reduced during stepwise infusion of rh-HGF in three of the four patients, whereas repeated doses of rh-HGF did not affect albuminuria. In the first patient, when BP decreased during rh-HGF administration, 200-300 mL of infusion was sufficient to restore BP immediately; prior infusion ameliorated HGF-induced BP reduction, as observed in preclinical animal experiments (Figure 1C). In any event, the decrease in BP observed during HGF infusion was reversible, and did not affect patients' general condition. Although patients 2 and 3, but not 4, also exhibited BP reduction during rh-HGF infusion, their general condition was stable without additional infusion or cessation of rh-HGF. Of particular importance, patient 2, who had awakened from hepatic encephalopathy, showed no symptom or sign during rh-HGF administration. Therefore, we concluded that rh-HGF administered intravenously with a stepwise increase for up to 14 consecutive days was very well tolerated.
In this study, although two of four patients survived, there was no evidence that rh-HGF was effective in improving outcome of patients with FHSA or LOHF. There are three potential reasons for the failure of this trial to demonstrate the efficacy of rh-HGF in patients with FH or LOHF.
First, the dose of rh-HGF and/or the 14-day treatment schedule used in this study might have been too low to produce beneficial effect. The dose chosen for this study was based on a scaling of the doses used in pre-clinical animal studies, and ensured safety in several repeated dose toxicity tests. Also, this dose, corresponding to 0.1 mg/kg in rodents, has been reported to accelerate liver regeneration in normal and partially hepatectomized rats . Conversely, the treatment duration was based on a nationwide survey of FH and LOHF in Japan between 1998 and 2002. In this survey, 90.4% (n = 47) of surviving patients from FHSA and LOHF (n = 52) awaked within 14 days after hepatic encephalopathy occurred, and 71% (n = 135) of non-surviving patients (n = 190) died within 28 days following the onset of hepatic encephalopathy. Therefore, rh-HGF administration for up to 14 days, followed by a 14-day observation period, was considered to be sufficient to evaluate both safety and efficacy. However, in the current study, there was no evidence of inhibited disease progression or stimulated liver regeneration. This suggests either that the dose of rh-HGF administered in this study was insufficient to induce liver regeneration and suppress liver injury, or that the 14-day treatment regimen was too short.
Second, HGF/c-Met pathways may be impaired in patients with FH or LOHF. When rh-HGF was intravenously injected in a bolus, most rh-HGF was distributed into the liver, and development of liver injury or cirrhosis retarded clearance of rh-HGF [23, 24]. In this clinical study, serum levels of HGF increased to 10-20 ng/mL (Cmax) just after a stepwise infusion of rh-HGF (0.6 mg/m2). HGF is known to stimulate proliferation of both mature hepatocytes and hepatic progenitor cells: less than 10 ng/mL of HGF was sufficient to induce proliferation of primary cultured rat hepatocytes [12, 25], and in vivo proliferation of rat hepatic progenitor cells was stimulated by serum levels of ~2 ng/mL human HGF [13, 26]. In patients with FH, serum levels of growth and growth-inhibitory factors were elevated [27–29], and reciprocal action of these factors in FH patients results in impaired liver regeneration. In this clinical trial, the increase in serum HGF concentration did not lead to improvement of hepatic reserve; furthermore, serum levels of transforming growth factor (TGF)-β, a growth-inhibitory factor, were not affected by HGF administration (Additional file 5). However, patient 1 revealed an increase in serum AFP, a marker of liver regeneration in patients with FH, during rh-HGF dosing period, and gradually decreased after the completion of rh-HGF administration. In contrast, patients 2 and 4, who survived, showed an increase in serum AFP at enrollment, but serum AFP levels decreased during the rh-HGF dosing period. These two patients received PSL in parallel with rh-HGF (Additional files 2 and 4); AFP expression is known to be affected by a glucocorticoid responsive element (GRE) present in the 5'-flanking region of AFP gene . Once serum AFP levels decreased, slowly tapered PSL did not affected serum AFP in these surviving patients. However, AFP expression at enrollment may be suppressed via the GRE, leading to a decrease in serum AFP levels. Therefore, dose escalation or prolonged exposure to rh-HGF may be able to overcome impaired liver regeneration.
Third, both FH and LOHF patients enrolled in this trial were predicted to die without liver transplantation; thus, the subjects already presented with an extremely serious condition. This life-threatening condition was influenced by the degree of impaired hepatic reserve and varying complications. Indeed, in this trial, all eligible patients with FH or LOHF developed hepatic encephalopathy, and the impaired hepatic reserve and general condition varied in severity. In these patients, even though safety could be evaluated, it may be difficult to evaluate the clinical efficacy. Therefore, it will be desirable to examine the clinical efficacy of rh-HGF in additional clinical trials involving patients with less severe conditions.
Systemic administration of potent growth factors could theoretically stimulate premalignant lesions in distant organs. Therefore, in this first clinical trial of rh-HGF, it was prudent to limit systemic therapy to life-threatening conditions. Although the two surviving patients in this study should be observed over the long term, we showed here that repeated doses of intravenous rh-HGF were well tolerated even in patients with a fatal disease. Recent investigations have indicated that HGF has the potential to improve treatment for intractable diseases of various organs, including the nervous system [31, 32], lung , heart [34–36], intestine [26, 37], kidney , and vessels . Therefore, the safety assessment of protein-based therapy of HGF described here sheds light on the development of new therapeutic modalities aimed at treating patients with intractable diseases.
Despite a mild BP reduction during rh-HGF infusion, intravenous rh-HGF at a dose of 0.6 mg/m2 was well tolerated in patients with FH or LOHF. However, there was no evidence that those dose of rh-HGF was effective for the treatment of these patients. Additional studies of rh-HGF at doses higher than 0.6 mg/m2, for longer periods, or in treatment of patients with less severe conditions, will be valuable in determining the clinical efficacy of rh-HGF.
We thank the study participants; the HGF-FH Clinical Study Team including Ms. Harue Tada, Ms. Akiko Matsuyama, Ms. Ikuyo Bando, Ms. Tomoko Yokota, Ms. Kazumi Miura, and Mr. Tatsuya Ito for implementation of the clinical trial; Dr. Hajime Segawa, Dr. Atsushi Fukatsu, Dr. Kazuki Ikeda, Dr. Hiroshi Ida, Dr. Eriko Sumi, and Dr. Ryujin Endo for support with patient consultations; Ms. Sayoko Ohara and Ms. Mai Kamiya for technical and secretarial assistance, respectively; Mitsubishi Tanabe Pharma Corporation for our supply of the active pharmaceutical ingredient of rh-HGF, its contracted preparation of GMP-grade formulation, and useful discussion about the results of preclinical safety tests; and the Intractable Hepato-biliary Disease Study Group of Japan for the data from a nationwide survey of FH and LOHF. This study was supported by funds from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
- O'Gray JG, Schalm SW, Williams R: Acute liver failure: redefining the syndromes. Lancet. 1993, 342: 273-10.1016/0140-6736(93)91818-7.View ArticleGoogle Scholar
- Lee WM, Squires RH, Nyberg SL, Doo E, Hoofnagle JH: Acute liver failure: summary of a workshop. Hepatology. 2008, 47: 1401-1415. 10.1002/hep.22177.PubMed CentralView ArticlePubMedGoogle Scholar
- Ichai P, Samuel D: Etiology and prognosis of fulminant hepatitis in adults. Liver Transpl. 2008, 14: S67-S79. 10.1002/lt.21612.View ArticlePubMedGoogle Scholar
- Fujiwara K, Mochida S, Matsui A, Nakayama N, Nagoshi S, Toda G: Intractable Liver Diseases Study Group of Japan, fulminant hepatitis and late onset hepatic failure in Japan. Hepatol Res. 2008, 38: 646-657. 10.1111/j.1872-034X.2008.00322.x.View ArticlePubMedGoogle Scholar
- Tygstrup N, Juhl E: Randomized trial of steroid therapy in acute liver failure. Report from the European Association for the Study of the Liver (EASL). Gut. 1979, 20: 620-623. 10.1136/gut.20.7.620.View ArticleGoogle Scholar
- Kumar M, Satapathy S, Monga R, Das K, Hissar S, Pande C, Sharma BC, Sarin SK: A randomized controlled trial of lamivudine to treat acute hepatitis B. Hepatology. 2007, 45: 97-101. 10.1002/hep.21486.View ArticlePubMedGoogle Scholar
- Clemmesen JO, Kondrup J, Nielsen LB, Larsen FS, Ott P: Effect of high-volume plasmapheresis on ammonia, urea, and amino acids in patients with acute liver failure. Am J Gastroenterol. 2001, 96: 1217-1223. 10.1111/j.1572-0241.2001.03706.x.View ArticlePubMedGoogle Scholar
- Gohda E, Tsubouchi H, Nakayama H, Hirono S, Takahashi K, Hashimoto S, Daikuhara Y: Human hepatocyte growth factor in plasma from patients with fulminant hepatic failure. Ex Cell Res. 1986, 166: 139-150. 10.1016/0014-4827(86)90514-8.View ArticleGoogle Scholar
- Gohda E, Tsubouchi H, Nakayama H, Hirono S, Sakiyama O, Takahashi K, Miyazaki H, Hashimoto S, Daikukhara Y: Purification and partial characterization of hepatocyte growth factor from plasma of patients with fulminant hepatic failure. J Clin Invest. 1988, 81: 414-419. 10.1172/JCI113334.PubMed CentralView ArticlePubMedGoogle Scholar
- Fujiwara K, Nagoshi S, Ohno A, Hirata K, Ohta Y, Mochida S, Tomiya T, Higashio K, Kurokawa K: Stimulation of liver growth by exogenous human hepatocyte growth factor in normal and partially hepatectomized rats. Hepatology. 1993, 18: 1443-1449. 10.1016/0270-9139(93)90237-H.View ArticlePubMedGoogle Scholar
- Ishii T, Sato M, Sudo K, Suzuki M, Nakai H, Hishida T, Niwa T, Umezu K, Yuasa S: Hepatocyte growth factor stimulates liver regeneration and elevates blood protein level in normal and partially hepatectomized rats. J Biochem. 1995, 117: 1105-1112.PubMedGoogle Scholar
- Moriuchi A, Hirono S, Ido A, Ochiai T, Nakama T, Uto H, Hori T, Hayashi K, Tsubouchi H: Additive and inhibitory effects of simultaneous treatment with growth factors on DNA synthesis through MAPK pathway and G1 cyclins in rat hepatocytes. Biochem Biophys Res Commun. 2001, 280: 368-373. 10.1006/bbrc.2000.4063.View ArticlePubMedGoogle Scholar
- Hasuike S, Ido A, Uto H, Moriuchi A, Tahara Y, Nagata K, Hori T, Hayashi K, Tsubouchi H: Hepatocyte growth factor accelerates the proliferation and differentiation of hepatic oval cells in a 2-acetylaminofluorene/partial hepatectomy model in rats. J Gastroenterol Hepatol. 2005, 20: 1753-1761. 10.1111/j.1440-1746.2005.03922.x.View ArticlePubMedGoogle Scholar
- Huh CG, Factor VM, Sanchez A, Uchida K, Conner EA, Thorgeirsson SS: Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci USA. 2004, 101: 4477-4482. 10.1073/pnas.0306068101.PubMed CentralView ArticlePubMedGoogle Scholar
- Borowiak M, Garratt AN, Wustefeld T, Strehle M, Trautwein C, Birchmeier C: Met provides essential signals for liver regeneration. Proc Natl Acad Sci USA. 2004, 101: 10608-10613. 10.1073/pnas.0403412101.PubMed CentralView ArticlePubMedGoogle Scholar
- Ozaki M, Haga S, Zhang HQ, Irani K, Suzuki S: Inhibition of hypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon rac1. Cell Death Differ. 2003, 10: 508-515. 10.1038/sj.cdd.4401172.View ArticlePubMedGoogle Scholar
- Schulze-Bergkamen H, Brenner D, Krueger A, Suess D, Fas SC, Frey CR, Dax A, Zink d, Buchler P, Muller M, Krammer PH: Hepatocyte growth factor induces Mcl-1 in primary human hepatocytes and inhibits CD95-mediated apoptosis via Akt. Hepatology. 2004, 39: 645-654. 10.1002/hep.20138.View ArticlePubMedGoogle Scholar
- Moumen A, Ieraci A, Patane S, Sole C, Comella JX, Dono R, Maina F: Met signals hepatocyte survival by preventing Fas-triggered FLIP degradation in a PI3K-Akt-dependent manner. Hepatology. 2007, 45: 1210-1217. 10.1002/hep.21604.View ArticlePubMedGoogle Scholar
- Okano J, Shiota G, Kawasaki H: Protective action of hepatocyte growth factor for liver injury caused by D-galactosamine in transgenic mice. Hepatology. 1997, 26: 241-1249. 10.1002/hep.510260136.View ArticleGoogle Scholar
- Kosai K, Matsumoto K, Nagata S, Tsujimoto Y, Nakamura T: Abrogation of Fas-induced fulminant hepatic failure in mice by hepatocyte growth factor. Biochem Biophys Res Commun. 1998, 244: 683-690. 10.1006/bbrc.1998.8293.View ArticlePubMedGoogle Scholar
- Kosai K, Matsumoto K, Funakoshi H, Nakamura T: Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice. Hepatology. 1999, 30: 51-159. 10.1002/hep.510300102.View ArticleGoogle Scholar
- Tsubouchi H, Niitani Y, Hirono S, Nakayama H, Gohda E, Arakaki N, Sakiyama O, Takahashi K, Kimoto M, Kawasaki S, Setoguchi M, Tachikawa T, Shin S, Arima T, Daikuhara Y: Levels of the human hepatocyte growth factor in serum of patients with various liver diseases determined by an enzyme-linked immunosorbent assay. Hepatology. 1991, 13: 1-5. 10.1002/hep.1840130102.View ArticlePubMedGoogle Scholar
- Ido A, Moriuchi A, Kim IL, Numata M, Nagata-Tsubouchi Y, Hasuike S, Uto H, Tsubouchi H: Pharmacokinetic study of recombinant human hepatocyte growth factor administered in a bolus intravenously or via portal vein. Hepatol Res. 2004, 30: 175-181. 10.1016/j.hepres.2004.09.002.View ArticlePubMedGoogle Scholar
- Kusumoto K, Ido A, Moriuchi A, Katsura T, Kim IL, Takahama Y, Numata M, Kodama M, Hasuike S, Nagata K, Uto H, Inui K, Tsubouchi H: Repeated intravenous injection of recombinant human hepatocyte growth factor ameliorates liver cirrhosis but causes albuminuria in rats. Int J Mol Med. 2006, 17: 503-509.PubMedGoogle Scholar
- Strain AJ, Ismail T, Tsubouchi H, Arakaki N, Hishida T, Kitamura N, Daikuhara Y, McMaster P: Native and recombinant human hepatocyte growth factors are highly potent promoters of DNA synthesis in both human and rat hepatocytes. J Clin Invest. 1991, 87: 1853-1857. 10.1172/JCI115207.PubMed CentralView ArticlePubMedGoogle Scholar
- Tahara Y, Ido A, Yamamoto S, Miyata Y, Uto H, Hori T, Hayashi K, Tsubouchi H: Hepatocyte growth factor facilitates colonic mucosal repair in experimental ulcerative colitis in rats. J Pharmacol Exp Ther. 2003, 307: 146-151. 10.1124/jpet.103.054106.View ArticlePubMedGoogle Scholar
- Tsubouchi H, Hirono S, Gohda E, Nakayama H, Takahashi K, Sakiyama O, Miyazaki H, Sugihara J, Tomita E, Muro Y, Daikuhara Y, Hashimoto S: Clinical significance of human hepatocyte growth factor in blood from patients with fulminant hepatic failure. Hepatology. 1989, 9: 875-881. 10.1002/hep.1840090615.View ArticlePubMedGoogle Scholar
- Tsubouchi H, Kawakami S, Hirono S, Miyazaki H, Kimoto M, Arima T, Sekiyama K, Yoshiba N, Arakaki Y, Daikuhara Y: Prediction of outcome in fulminant hepatic failure by serum human hepatocyte growth factor. Lancet. 1992, 340: 307-10.1016/0140-6736(92)92396-W.View ArticlePubMedGoogle Scholar
- Eguchi S, Okudaira S, Azuma T, Ohno Y, Fujioka H, Furui J, Tanaka K, Kanematsu T: Changes in liver regenerative factors in a case of living-related liver transplantation. Clin Tlanspl. 1999, 13: 536-544. 10.1034/j.1399-0012.1999.130616.x.View ArticleGoogle Scholar
- Ido A, Nakata K, Kato Y, Nakao K, Murata K, Fujita M, Ishii N, Tamaoki T, Shiku H, Nagataki S: Gene therapy for hepatoma cells using a retrovirus vector carrying herpes simplex virus thymidine kinase gene under the control of human alpha-fetoprotein gene promoter. Cancer Res. 1995, 55: 3105-3109.PubMedGoogle Scholar
- Tsuzuki N, Miyazawa T, Matsumoto K, Nakamura T, Shima K: Hepatocyte growth factor reduces the infarct volume after transient focal cerebral ischemia in rats. Neurol Res. 2001, 23: 417-424. 10.1179/016164101101198659.View ArticlePubMedGoogle Scholar
- Sun W, Funakoshi H, Nakamura T: Overexpression of HGF retards disease progression and prolongs life span in a transgenic mouse model of ALS. J Neurosci. 2002, 22: 6537-6548.PubMedGoogle Scholar
- Yaekashiwa M, Nakayama S, Ohnuma K, Sakai T, Abe T, Satoh K, Matsumoto K, Nakamura T, Takahashi T, Nukiwa T: Simultaneous or delayed administration of hepatocyte growth factor equally represses the fibrotic changes in murine lung injury induced by bleomycin. A morphogenic study. Am J Respir Crit Care Med. 1997, 156: 1937-1944.View ArticlePubMedGoogle Scholar
- Ueda H, Sawa Y, Matsumoto K, Kitagawa-Sakakida S, Kawahira Y, Nakamura T, Kaneda Y, Matsuda H: Gene transfection of hepatocyte growth factor attenuates reperfusion injury in the heart. Ann Thorac Surg. 1999, 67: 1726-1731. 10.1016/S0003-4975(99)00279-9.View ArticlePubMedGoogle Scholar
- Miyagawa S, Sawa Y, Taketani S, Kawaguchi N, Nakamura T, Matsuura N, Matsuda H: Myocardial regeneration therapy for heart failure: hepatycte growth factor enhances the effect of cellular cardiomyoplasty. Circulation. 2002, 105: 2556-2561. 10.1161/01.CIR.0000016722.37138.F2.View ArticlePubMedGoogle Scholar
- Morishita R, Nakamura S, Hayashi S, Taniyama Y, Moriguchi A, Nagano T, Taiji M, Noguchi H, Takeshita S, Matsumoto K, Nakamura T, Higaki J, Ogihara T: Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as cytokine supplement therapy. Hypertension. 1999, 33: 1379-1384.View ArticlePubMedGoogle Scholar
- Numata M, Ido A, Moriuchi A, Kim IL, Tahara Y, Yamamoto S, Hasuike S, Nagata K, Miyata Y, Uto H, Tsubouchi H: Hepatocyte growth factor facilitates the repair of large colonic ulcers in 2,4,6-trinitrobenzene sulfonic acid-induced colitis in rats. Inflamm Bowel Dis. 2005, 11: 551-518. 10.1097/01.MIB.0000164192.71381.5c.View ArticlePubMedGoogle Scholar
- Kawaida K, Matsumoto K, Shimazu H, Nakamura T: Hepatocyte growth factor prevents acute renal failure and accelerates renal regeneration in mice. Proc Natl Acad Sci USA. 1994, 91: 4357-4361. 10.1073/pnas.91.10.4357.PubMed CentralView ArticlePubMedGoogle Scholar
- Morishita R, Aoki M, Hashiya N, Makino H, Yamasaki K, Azuma J, Sawa Y, Matsuda H, Kaneda Y, Ogihara T: Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease. Hypertension. 2004, 44: 203-209. 10.1161/01.HYP.0000136394.08900.ed.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.