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Tangtrongchitr P, Poomsawat S, Chongsrisawat V, Honsawek S, Poovorawan Y, Chongpison Y, Vejchapipat P. Hepatic expression of HGF/C-met and native liver survival in biliary atresia. Pediatr Surg Int 2020; 36:597-602. [PMID: 32200404 DOI: 10.1007/s00383-020-04643-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/05/2020] [Indexed: 01/20/2023]
Abstract
BACKGROUND The prognosis of biliary atresia (BA) remains difficult to predict. This study evaluated the roles of hepatocyte growth factor (HGF) and its receptor (C-met) towards clinical outcome and native liver survival. METHODS Hepatic HGF and C-met expression were determined using immunohistochemistry from liver biopsies of 41 BA patients during Kasai operation, and 17 non-cholestatic patients. The HGF and C-met expression was visually scored as per its intensity and percentage of stained area. BA patients were classified as high- and low-HGF and C-met receptor status. Native liver survival was compared between the two groups at 3-year follow-up. Data are shown as median and range. MAIN RESULTS Median age of BA patients was 2 (1-6) months. Hepatic HGF and C-met staining scores of BA patients were higher than those of non-cholestatic patients (P < 0.0001). There was a correlation between HGF and C-met staining scores (spearman r = 0.77, P < 0.0001). However, there was no association between their expression and early outcome at 6 months post-op. Mean follow-up time was 68.6 months. Survival analysis revealed that native liver survival at 1 year and 3 years were 88% and 77%, respectively. Additionally, 82.6% (19/23) of patients in the low-HGF group survived with native liver, compared with 66.7% (10/15) of those in high-HGF group (P = 0.436). For C-met expression, 78.6% (22/28) of low-score and 70% (7/10) of high score groups survived with native liver (P = 0.673). CONCLUSIONS Strong expression of hepatic HGF and its receptor in BA patients was demonstrated. However, the expression was not associated with the early outcome and native liver survival. These results suggest that HGF involved in the liver pathology of BA but its expression cannot be used as a prognostic indicator. Small sample size of patients was a main limitation. Further studies are warranted to validate our findings.
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Affiliation(s)
| | - Sopee Poomsawat
- Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
| | - Voranush Chongsrisawat
- Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Sittisak Honsawek
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Yong Poovorawan
- Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Yuda Chongpison
- Biostatistics Division, Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Paisarn Vejchapipat
- Department of Surgery, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
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Li TT, An JX, Xu JY, Tuo BG. Overview of organic anion transporters and organic anion transporter polypeptides and their roles in the liver. World J Clin Cases 2019; 7:3915-3933. [PMID: 31832394 PMCID: PMC6906560 DOI: 10.12998/wjcc.v7.i23.3915] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 11/20/2019] [Accepted: 11/26/2019] [Indexed: 02/05/2023] Open
Abstract
Organic anion transporters (OATs) and organic anion transporter polypeptides (OATPs) are classified within two SLC superfamilies, namely, the SLC22A superfamily and the SLCO superfamily (formerly the SLC21A family), respectively. They are expressed in many tissues, such as the liver and kidney, and mediate the absorption and excretion of many endogenous and exogenous substances, including various drugs. Most are composed of 12 transmembrane polypeptide chains with the C-terminus and the N-terminus located in the cell cytoplasm. OATs and OATPs are abundantly expressed in the liver, where they mainly promote the uptake of various endogenous substrates such as bile acids and various exogenous drugs such as antifibrotic and anticancer drugs. However, differences in the locations of glycosylation sites, phosphorylation sites, and amino acids in the OAT and OATP structures lead to different substrates being transported to the liver, which ultimately results in their different roles in the liver. To date, few articles have addressed these aspects of OAT and OATP structures, and we study further the similarities and differences in their structures, tissue distribution, substrates, and roles in liver diseases.
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Affiliation(s)
- Ting-Ting Li
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi 563100, Guizhou Province, China
| | - Jia-Xing An
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi 563100, Guizhou Province, China
| | - Jing-Yu Xu
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi 563100, Guizhou Province, China
| | - Bi-Guang Tuo
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi 563100, Guizhou Province, China
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3
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Triazolopyridazine derivatives: Synthesis, cytotoxic evaluation, c-Met kinase activity and molecular docking. Bioorg Chem 2019; 92:103272. [DOI: 10.1016/j.bioorg.2019.103272] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 08/15/2019] [Accepted: 09/09/2019] [Indexed: 01/02/2023]
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The recovery of the PT-INR to less than 1.3 predicts survival in patients with severe acute liver injury. J Gastroenterol 2018; 53:861-872. [PMID: 29260300 DOI: 10.1007/s00535-017-1421-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 12/03/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND Acute liver failure is a potentially fatal disease of various etiologies for which liver transplantation is the only known curative treatment. Although the decision-making on transplantation is largely dependent on the severity of liver injury (based on predicting a fatal outcome), a statistical analysis to predict "survival" has not been extensively conducted. In this study, we investigate the medical history of patients in two distinct areas of Japan with the aim of identifying the predictors of survival in patients with acute liver injury (ALI). METHODS Datasets of 301 patients with ALI in two distinct areas (93 in southern Kyushu and 208 in northern Tohoku) of Japan, who were treated from 2004 to 2014, were included in the analysis. RESULTS Among the enrolled 301 cases, 263 patients survived without transplantation. A PT-INR of ≥ 1.3 during the clinical course was found to be adequate for predicting a poor prognosis, because all of the fatal cases emerged from this population (hazard ratios: southern Kyushu, 0.2827; northern Tohoku, 0.1862). All surviving patients showed a reduction in their PT-INR during treatment, whereas the PT-INR did not decrease in the patients with a poor prognosis. A PT-INR of < 1.3 on days 7 and 8 efficiently predicted transplant-free survival (log-rank test: southern Kyushu, P = 0.0030; northern Tohoku, P = 0.0022). CONCLUSIONS A PT-INR of ≥ 1.3 during the clinical course might identify cases with a poor prognosis, while the recovery of the PT-INR to < 1.3 predicts transplant-free survival.
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Abstract
Background/Aims To date, numerous studies have demonstrated that several angiogenesis regulators circulate in the blood and may function as endocrine factors in cancer patients. This review aims to give a comprehensive insight into the possible clinical value of circulating angiogenesis regulators, mainly basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF), angiogenin, pleiotrophin, thrombospondin (TSP) and endostatin (ES) in cancer patients. Methods A computerized (MEDLINE) and a manual search based on the reference lists of the publications were performed to identify articles published on this topic. Results In a detailed literature search, approximately 100 publications were found up to the end of 1999. Circulating angiogenic factors such as bFGF, VEGF, HGF and angiogenin have been evaluated not only as diagnostic and/or prognostic factors but also as predictive factors in cancer patients. On the other hand, little is known about the clinical significance of negative regulators. Neither the source nor the mechanism of protein externalization has been clarified in detail. Conclusions Although there are no known factors with established clinical utility, circulating angiogenesis regulators may be useful in several situations. They could be used to determine the risk of developing cancer, to screen for early detection, to distinguish benign from malignant disease, and to distinguish between different types of malignancies. In patients with established malignancies such factors might be used to determine prognosis, to predict the response to therapy, and to monitor the clinical course. Further investigations are warranted to assess the specific utility of each factor.
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Affiliation(s)
- K Kuroi
- Department of Surgery, Tokyo Metropolitan Komagome Hospital, Japan.
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Miwa Y, Ellis A, Hughes R, Langley P, Wendon J, Williams R. Effect of ELAD Liver Support on Plasma HGF and TGF–β1 in Acute Liver Failure. Int J Artif Organs 2018. [DOI: 10.1177/039139889601900406] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The aim of this study was to investigate the effects of treatment with the extracorporeal liver assist device (ELAD) in patients with acute liver failure (ALF) on plasma hepatocyte growth factor (HGF), the most potent growth factor, and transforming growth factor-β1 (TGF-β1), an inhibitory factor for liver regeneration. Initial plasma HGF, measured by ELISA, was significantly increased in the ALF patients (7.86 ± SEM 1.76 ng/ml) compared with normal subjects (0.10 ± 0.02 ng/ml, p<0.001). After 6 hours of ELAD haemoperfusion, plasma HGF increased further (30.5 ± 6.19 ng/ml, p<0.001), with a subsequent decrease towards the initial value by 48 hours. Initial plasma levels of TGF-β1 determined by ELISA were significantly increased in the ALF patients (43.4 ± 5.9 ng/ml) compared with normal subjects (25.1 ± 2.3 ng/ml, p<0.01), but there was no change in plasma TGF-β1 during the study period in either the ELAD or control ALF group. As HGF is a heparin-binding growth factor and similar changes in HGF were observed during CVVHD, one possible explanation is that heparin administered as anticoagulant for extracorporeal circulation is involved in the effects observed on HGF.
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Affiliation(s)
- Y. Miwa
- Institute of Liver Studies, King's College School of Medicine & Dentistry, London - UK
| | - A.J. Ellis
- Institute of Liver Studies, King's College School of Medicine & Dentistry, London - UK
| | - R.D. Hughes
- Institute of Liver Studies, King's College School of Medicine & Dentistry, London - UK
| | - P.G. Langley
- Institute of Liver Studies, King's College School of Medicine & Dentistry, London - UK
| | - J.A. Wendon
- Institute of Liver Studies, King's College School of Medicine & Dentistry, London - UK
| | - R. Williams
- Institute of Liver Studies, King's College School of Medicine & Dentistry, London - UK
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Yamazaki T, Wakai M, Enosawa S, Tokiwa T. Analysis of soluble factors in conditioned media derived from primary cultures of cirrhotic liver of biliary atresia. In Vitro Cell Dev Biol Anim 2017; 53:564-573. [PMID: 28364348 DOI: 10.1007/s11626-017-0144-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Accepted: 02/20/2017] [Indexed: 01/31/2023]
Abstract
Biliary atresia (BA) is a rare and serious liver disease in newborn infants. Previously, we reported that non-parenchymal cell (NPC) fractions from cirrhotic liver of BA may contain hepatic stem/progenitor cells in primary culture of NPC fractions. In this study, NPC fractions were subjected to primary or passage culture and found that clusters of hepatocyte-like cells appear even without adding hepatocyte growth factor (HGF) to the culture medium, but not in their passage culture used as a control. Based on these findings, conditioned media (CMs) were collected and soluble factors in the CMs were analyzed in order to elucidate the mechanism of the appearance of hepatocyte-like cells or their clusters. A large amount of active HGF consisting of α and β chains was detected in CMs derived from primary culture, but not in CMs from passage culture, as determined by western blot analysis, bone morphogenetic protein (BMP)-4, oncostatin M (OSM), and transforming growth factor (TGF)-β1 were not detected in any of the CMs. The number of hepatocyte-like cells in primary culture tended to decrease following treatment with the HGF receptor c-Met inhibitor, SU11274 in a dose-dependent manner. Furthermore, the clusters of hepatocyte-like cells tended to increase in size and number when freshly isolated NPC fractions were cultured in the presence of 10% of CMs collected after 3-4 wk of primary culture. In conclusion, these findings indicate that CMs derived from primary culture of NPC fractions of BA liver contain a large amount of active HGF, which may activate hepatic stem/progenitor cells and promote the appearance of hepatocyte-like cells or their clusters through HGF/c-Met signaling. The present study would lead to cell therapy using the patient's own cells for the treatment of BA.
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Affiliation(s)
- Taisuke Yamazaki
- Department of Liver Cell Biology, Kohno Clinical Medicine Research Institute, Tokyo, Japan.
| | - Mariko Wakai
- Department of Liver Cell Biology, Kohno Clinical Medicine Research Institute, Tokyo, Japan
| | - Shin Enosawa
- Division for Advanced Medical Sciences, National Center for Child Health and Development, Tokyo, Japan
| | - Takayoshi Tokiwa
- Department of Liver Cell Biology, Kohno Clinical Medicine Research Institute, Tokyo, Japan
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8
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Mizuno S, Das BC, Iizawa Y, Kato H, Murata Y, Tanemura A, Kuriyama N, Azumi Y, Kishiwada M, Usui M, Sakurai H, Isaji S. Pretransplant Serum Hyaluronic Acid Can Be a Biomarker as a Prognostic Predictor in Adult-to-Adult Living Donor Liver Transplantation. Transplant Proc 2017; 49:102-108. [PMID: 28104115 DOI: 10.1016/j.transproceed.2016.11.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
OBJECTIVE The goal of this study was to evaluate whether pretransplant serum hyaluronic acid (HA) levels can predict outcomes after adult-to-adult living donor liver transplantation (LDLT). METHODS In study I, 21 patients who underwent LDLT (March 2002-February 2004) were divided into 2 groups: the H-I group (HA ≥500 ng/mL; n = 12) and the L-I group (HA <500 ng/mL; n = 9). The influence of pretransplantation HA levels on short-term surgical outcome was investigated. In study II, 77 LDLT patients (May 2004-December 2014) were also divided into 2 groups: the H-II group (HA ≥500 ng/mL; n = 40) and the L-II group (HA <500 ng/mL; n = 37). We compared long-term survival and investigated prognostic factors. RESULTS In study I, HA levels significantly decreased after LDLT, and those in the H-I group were significantly higher compared with the L-I group at 1, 3, 5, and 7 days after LDLT. There were significant differences in postoperative peak total bilirubin levels (H-I vs L-I, 17.2 vs 6.2 mg/dL; P = .013), peak ascitic fluid volume (1327 vs 697 mL/d; P = .005), and the hepatocyte growth factor levels at 3 days after LDLT (1879 vs 1092 pg/mL; P = .03). In study II, the 1- and 5-year survival rates were significantly lower in the H-II group than in the L-II group (H-II vs L-II, 65.0% and 48.5% vs 86.5% and 80.8%; P = .004). In multivariate analysis, significant prognostic factors were preoperative HA ≥500 ng/mL (P = .004) and graft to recipient body weight ratio <0.8 (P = .042). CONCLUSIONS Preoperative HA level can be a prognostic risk factor. Patients with high HA levels are vulnerable and should be carefully managed after LDLT.
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Affiliation(s)
- S Mizuno
- Hepatobiliary-Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan.
| | - B C Das
- Hepatobiliary Pancreatic Surgery, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Y Iizawa
- Hepatobiliary-Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - H Kato
- Hepatobiliary-Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Y Murata
- Hepatobiliary-Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - A Tanemura
- Hepatobiliary-Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - N Kuriyama
- Hepatobiliary-Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Y Azumi
- Hepatobiliary-Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - M Kishiwada
- Hepatobiliary-Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - M Usui
- Hepatobiliary-Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - H Sakurai
- Hepatobiliary-Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - S Isaji
- Hepatobiliary-Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
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Kuroda H, Kakisaka K, Oikawa T, Onodera M, Miyamoto Y, Sawara K, Endo R, Suzuki K, Takikawa Y. Liver stiffness measured by acoustic radiation force impulse elastography reflects the severity of liver damage and prognosis in patients with acute liver failure. Hepatol Res 2015; 45:571-7. [PMID: 25041122 DOI: 10.1111/hepr.12389] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 07/02/2014] [Accepted: 07/06/2014] [Indexed: 02/01/2023]
Abstract
AIM We measured liver stiffness (LS) in patients with acute liver failure (ALF) using acoustic radiation force impulse (ARFI) elastography and investigated the usefulness of measuring LS for predicting the prognosis of ALF patients. METHODS From April 2010 to December 2013, we evaluated 63 patients with acute liver disease. The subjects included 41 patients with acute hepatitis (AH), 16 patients with severe AH (SAH), who had no hepatic encephalopathy despite plasma prothrombin time of 40% or less, and six patients with fulminant hepatitis (FH) diagnosed according to the criteria of the Japanese Study Group. The relationships among shear wave velocity (SWV), clinical diagnosis, liver function tests and prognosis were evaluated. Receiver-operator curve (ROC) analysis was performed to investigate whether ARFI elastography exhibits potential usefulness for the prediction of FH. RESULTS The mean SWV on admission were 1.98 ± 0.55, 2.61 ± 0.58 and 3.66 ± 0.86 m/s in the AH, SAH and FH groups, respectively. The SWV was significantly higher in the FH group than in the other groups (P < 0.001), and in the SAH group than in the AH group (P = 0.002). The area under the ROC for predicting FH was 0.924 (sensitivity, 83.3%; specificity, 93.0%). The SWV was significantly increased in non-survivors, while remaining decreased in survivors (P = 0.002). CONCLUSION The SWV measured by ARFI elastography reflects severity of liver damage, and serial changes in SWV predict the prognosis of ALF patients. The SWV is an early and precise biomarker of FH.
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Affiliation(s)
- Hidekatsu Kuroda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan
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Maroun CR, Rowlands T. The Met receptor tyrosine kinase: a key player in oncogenesis and drug resistance. Pharmacol Ther 2013; 142:316-38. [PMID: 24384534 DOI: 10.1016/j.pharmthera.2013.12.014] [Citation(s) in RCA: 164] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Accepted: 12/12/2013] [Indexed: 12/14/2022]
Abstract
The Met receptor tyrosine kinase (RTK) is an attractive oncology therapeutic target. Met and its ligand, HGF, play a central role in signaling pathways that are exploited during the oncogenic process, including regulation of cell proliferation, invasion, angiogenesis, and cancer stem cell regulation. Elevated Met and HGF as well as numerous Met genetic alterations have been reported in human cancers and correlate with poor outcome. Alterations of pathways that regulate Met, such as the ubiquitin ligase c-Cbl are also likely to activate Met in the oncogenic setting. Moreover, interactive crosstalk between Met and other receptors such as EGFR, HER2 and VEGFR, underlies a key role for Met in resistance to other RTK-targeted therapies. A large body of preclinical and clinical data exists that supports the use of either antibodies or small molecule inhibitors that target Met or HGF as oncology therapeutics. The prognostic potential of Met expression has been suggested from studies in numerous cancers including lung, renal, liver, head and neck, stomach, and breast. Clinical trials using Met inhibitors indicate that the level of Met expression is a determinant of trial outcome, a finding that is actively under investigation in multiple clinical scenarios. Research in Met prognostics and predictors of drug response is now shifting toward more sophisticated methodologies suitable for development as validated and effective biomarkers that can be partnered with therapeutics to improve patient survival.
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Affiliation(s)
- Christiane R Maroun
- Mirati Therapeutics, 7150 Frederick-Banting, Suite 200, Montreal, Quebec H4S 2A1, Canada.
| | - Tracey Rowlands
- Mirati Therapeutics, 7150 Frederick-Banting, Suite 200, Montreal, Quebec H4S 2A1, Canada
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Nucleus number in clusters of transplanted fetal liver cells increases by partial hepatectomy of recipient rats. J Biosci Bioeng 2013; 115:568-70. [DOI: 10.1016/j.jbiosc.2012.11.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Revised: 10/31/2012] [Accepted: 11/19/2012] [Indexed: 11/20/2022]
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Sugiura Y, Hiramatsu K, Hamauzu R, Motoki T, Miyazaki M, Uto H, Tsubouchi H, Tanaka S, Gohda E. Mitogen-activated protein kinases-dependent induction of hepatocyte growth factor production in human dermal fibroblasts by the antibiotic polymyxin B. Cytokine 2012; 60:205-11. [PMID: 22749438 DOI: 10.1016/j.cyto.2012.06.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2011] [Revised: 05/03/2012] [Accepted: 06/04/2012] [Indexed: 02/02/2023]
Abstract
Hepatocyte growth factor (HGF) stimulates migration and proliferation of keratinocytes and has been suggested to be involved in wound healing. The cationic antibiotic polymyxin B (PMB) is commonly used as a topical antibiotic for wound care. If PMB possesses an HGF-inducing activity, the antibiotic is potentially beneficial for wound healing in addition to minimizing chances of infection. In this study, we found that PMB markedly induced HGF production from various types of cells including human dermal fibroblasts. Its effect was stronger than the effects of epidermal growth factor and cholera toxin and was comparable to the effect of 8-bromo-cAMP. Among the polymyxin family and polymyxin derivatives, colistin was also effective, whereas colistin methanesulfonate had only a marginal effect and PMB nonapeptide was ineffective. The stimulatory effect of PMB was accompanied by upregulation of HGF gene expression. Increase in phosphorylation of extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) was observed from 0.25 h to 6h after the addition of PMB, while increase in phosphorylation of p38 mitogen-activated protein kinase (MAPK) was detected from 24h to 60 h after PMB addition. The MAPK/ERK kinase inhibitor PD98059, the JNK inhibitor SP600125 and the p38 MAPK inhibitor SB203580 all potently inhibited PMB-induced HGF production. Lastly, proliferation of human dermal fibroblasts was significantly stimulated by PMB. These results indicate that PMB-induced HGF production and proliferation of human dermal fibroblasts and suggest that activation of MAPKs is involved in the induction of HGF production.
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Affiliation(s)
- Yoshihiro Sugiura
- Department of Immunochemistry, Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
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Abstract
BACKGROUND Angiogenic factors are involved in the physiopathology of several inflammatory diseases and they probably play a role in the pathogenesis of acute pancreatitis (AP). AIMS To investigate if angiogenic factors are elevated in patients with AP, their relationship with severity and clinical evolution of AP, and their use as prognosis markers of AP. METHODS A case (25)-control (30) study was carried out. Patients with AP were classified according to severity (using Ranson and Glasgow scores) and according to their clinical evolution (taking into account the development of complications during hospital stay). Platelet-derived growth factor (PDGFBB), angiopoietin-1, angiopoietin-2 (Ang-2), angiopoietin tyrosine-kinase receptor, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), VEGF tyrosine-kinase receptor 1, and VEGF tyrosine-kinase receptor 2 were determined at 12 hours and then at 5 days after hospitalization. RESULTS PDGFBB, Ang-2, angiopoietin tyrosine-kinase receptor, and HGF were significantly higher in cases (P<0.001), and in patients with unfavorable clinical evolution (P<0.001). PDGFBB and HGF were significantly higher in patients with severe AP (P<0.05). To predict unfavorable clinical evolution, PDGFBB, Ang-2, and HGF showed an area under receiver operating characteristic curve of 0.97. CONCLUSIONS PDGFBB and HGF are related to severity of AP. These factors along with Ang-2 are related to clinical evolution and are useful in predicting the development of several complications during hospital stay. Therefore, these angiogenic factors could be useful as prognosis markers of AP.
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Setoyama H, Ido A, Numata M, Moriuchi A, Yamaji N, Tamai T, Funakawa K, Fujita H, Sakiyama T, Uto H, Oketani M, Tsubouchi H. Repeated enemas with hepatocyte growth factor selectively stimulate epithelial cell proliferation of injured mucosa in rats with experimental colitis. Life Sci 2011; 89:269-75. [PMID: 21763320 DOI: 10.1016/j.lfs.2011.06.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2010] [Revised: 06/04/2011] [Accepted: 06/08/2011] [Indexed: 01/27/2023]
Abstract
AIMS Hepatocyte growth factor (HGF) modulates intestinal epithelial cell proliferation and migration. We previously reported that systemic administration of recombinant human HGF (rh-HGF) ameliorated experimental colitis. However, an increase in serum HGF concentrations may induce undesired systemic effects, limiting the use of rh-HGF. To avoid possible side effects, we investigated the safety and efficacy of rectally administered rh-HGF as a treatment for experimental colitis. MAIN METHODS We measured serum human HGF concentration following a single rectal enema of rh-HGF. Rats with 2,4,6-trinitrobenzene sulfonic acid (TNBS)- or dextran sulfate sodium (DSS)-induced colitis were treated with rectal enemas of rh-HGF once a day for seven days. The degree of mucosal injuries and the proliferative activity of the colon epithelium were examined. KEY FINDINGS Rats administered a rectal enema of rh-HGF at a dose of 0.1 mg/ml or less had no detectable rh-HGF in the serum. Repeated enemas of rh-HGF at this dose significantly reduced mucosal injuries, both with respect to lesion size and inflammatory cell infiltration. This regimen also stimulated proliferation of epithelial cells surrounding injured mucosa; however, the cell proliferation of uninjured mucosa was not affected by this local treatment. SIGNIFICANCE Rectally administered rh-HGF selectively accelerates the repair of injured mucosa in rat experimental colitis without systemic exposure to HGF. Rectal enemas of HGF are thus a potential novel and safe therapy for IBD.
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Affiliation(s)
- Hitoshi Setoyama
- HGF Hepatic Regeneration Therapy Project, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto, Japan
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Ido A, Moriuchi A, Numata M, Murayama T, Teramukai S, Marusawa H, Yamaji N, Setoyama H, Kim ID, Chiba T, Higuchi S, Yokode M, Fukushima M, Shimizu A, Tsubouchi H. 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. J Transl Med 2011; 9:55. [PMID: 21548996 PMCID: PMC3112439 DOI: 10.1186/1479-5876-9-55] [Citation(s) in RCA: 133] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Accepted: 05/08/2011] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Affiliation(s)
- Akio Ido
- HGF Hepatic Regeneration Therapy Project, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto, Japan.
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16
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Correlation between serum hepatocyte growth factor level and percutaneous coronary balloon angioplasty: An alternative mechanism of reduction in restenosis with citostazol. Int J Angiol 2011. [DOI: 10.1007/bf01637048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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Anan F, Masaki T, Jikumaru K, Iwao T, Eshima N, Saikawa T, Yoshimatsu H. Hepatocyte growth factor is a significant risk factor for white matter lesions in Japanese type 2 diabetic patients. Eur J Clin Invest 2010; 40:585-90. [PMID: 20497462 DOI: 10.1111/j.1365-2362.2010.02301.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND The presence of white matter lesions (WML) is an important prognostic factor for the development of stroke. Elevated hepatocyte growth factor (HGF) levels are associated with a high mortality rate in type 2 diabetic patients. The preliminary study was therefore designed to test the hypothesis that the presence of WML correlates with HGF and insulin resistance in type 2 diabetic patients not receiving insulin treatment. MATERIAL AND METHODS Based on brain magnetic resonance imaging, 92 type 2 diabetic patients were divided into two groups: WML-positive group (age 60 +/- 5 years, mean +/- SD, n = 35) and WML-negative group (age 59 +/- 6 years, mean +/- SD, n = 57. The level of blood glucose was assessed by fasting plasma glucose, fasting immunoreactive insulin, homeostasis model assessment (HOMA) index and haemoglobin A1c (HbA1c). RESULTS The body mass index was higher in the WML-positive group than that in the WML-negative group (P < 0.005). Plasma levels of triglycerides were higher while high-density lipoprotein cholesterol was lower in the WML-positive group than in the WML-negative group (P < 0.01 and P < 0.0001 respectively). Fasting plasma glucose (P < 0.0001), insulin concentrations (P < 0.0001), HOMA index (P < 0.0001) and HGF (< 0.0001) levels were higher in the WML-positive group than in the WML-negative group. Multivariate logistic analysis revealed that WML was independently predicted by the high HGF and insulin resistance (P < 0.0001 and P < 0.0001 respectively). CONCLUSION The results of this preliminary study indicate that the presence of WML was associated with the high HGF and insulin resistance in Japanese patients with type 2 diabetes mellitus.
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Affiliation(s)
- Futoshi Anan
- Department of Cardiology, Oita Red Cross Hospital, Oita, Japan.
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Afford SC, Kakoullis T, Oates J, Crocker J, Strain AJ. Effects of hepatocyte growth factor on differentiation and cMET receptor expression in the promyelocytic HL60 cell line. Mol Pathol 2010; 48:M23-7. [PMID: 16695971 PMCID: PMC407915 DOI: 10.1136/mp.48.1.m23] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Aim-To determine the effects of hepatocyte growth factor (HGF) on myeloid cell differentiation and cMET expression using the promyelocytic HL60 cell line.Methods-HL60 cells cultured with purified recombinant HGF, dimethyl sulphoxide (DMSO), or 12-O tetradecanoylphorbol-13-acetate (TPA) were immunostained for the differentiation markers, human neutrophil elastase (HNE), cathepsin B, MAC387, or the receptor for hepatocyte growth factor (cMET).Results-HGF treated cells were positive on staining for cathepsin B and MAC387, but were negative for HNE, indicating monocytic differentiation. HGF treated cells had the morphology of monocytes but continued to divide at the same rate as control cells and remained non-adherent. DMSO treated cells were positive for HNE and cell numbers were reduced, confirming myeloid differentiation. TPA treated cells were positive for cathepsin B and MAC387, cell numbers were reduced, and the cells became adherent, confirming terminal monocytic differentiation. Untreated HL60 cells were weakly positive for cMET at the start of the culture period and expression increased after 72 hours. Cells treated with HGF, DMSO, or TPA were also positive for cMET.Conclusions-These data suggest that HGF induced partial monocytic differentiation in HL60 cells. In addition, expression of cMET by HL60 cells occurs at an early stage in myelomonocytic cells and is maintained after differentiation along either the myeloid or monocytic pathways.
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Affiliation(s)
- S C Afford
- The Liver Research Laboratories, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH
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Barril G, Bartolomé J, Sanz P, Buoncristiani E, Traver JA, Selgas R, Buoncristiani U, Castillo I, Quiroga JA, Carreño V. Effect of hemodialysis schedules and membranes on hepatocyte growth factor and hepatitis C virus RNA levels. J Med Virol 2010; 82:763-7. [PMID: 20336716 DOI: 10.1002/jmv.21469] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Hemodialysis induces production of the hepatocyte growth factor (HGF) and decrease of serum hepatitis C virus (HCV) RNA in patients with HCV infection, but it is not known if the hemodialysis schedule or type of membrane affect both the HGF production and HCV viremia. The effects on both parameters of alternate-day intermittent hemodialysis and short-daily hemodialysis and high and low flux membranes were investigated in 41 patients treated by hemodialysis. Sixteen (39%) patients were anti-HCV positive and 11 (69%) had HCV RNA. Twenty-six patients were on alternate-day intermittent and 15 on short-daily hemodialysis. High flux membranes were used for 29 patients and low flux membranes for 12 patients. A decrease in HCV RNA was observed at the end of hemodialysis (8.6 x 10(5) +/- 1.1 x 10(6) IU/ml vs. 4.4 x 10(5) +/- 7.3 x 10(5) IU/ml, P = 0.003). The proportion of HCV RNA decrease was similar in patients dialyzed with both schedules and with both types of membranes. The HGF levels increased from 2,605.9 +/- 1,428.7 to >8,000 pg/ml at 15 min. At the end of the session, the HGF levels decreased to 5,106.7 +/- 2,533.9 pg/ml. The HGF levels at the start of the next session were similar to those at baseline (2,680.0 +/- 1,209.3 pg/ml). The increase and dynamics of the HGF levels were similar in patient's hemodialyzed with both schedules and with both types of membranes. These results suggest that changes in HCV RNA and HGF levels during hemodialysis are not influenced by the schedule or type of membrane used.
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Affiliation(s)
- Guillermina Barril
- Department of Nephrology, Hospital Universitario de la Princesa, Madrid, Spain
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20
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Voraphani N, Theamboonlers A, Khongphatthanayothin A, Srisai C, Poovorawan Y. Increased level of hepatocyte growth factor in children with dengue virus infection. ANNALS OF TROPICAL PAEDIATRICS 2010; 30:213-218. [PMID: 20828454 DOI: 10.1179/146532810x12786388978607] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
BACKGROUND Evidence of hepatocellular damage is common in dengue-infected individuals. Hepatocyte growth factor (HGF), a key cytokine responsible for liver regeneration, may play a prognostic role in dengue virus infection. AIM To determine the relationship between serum HGF level and disease severity in patients with dengue virus infection. METHODS Serum samples from 27 children [17 dengue fever (DF), ten dengue haemorrhagic fever (DHF)] with serologically confirmed dengue virus infection during the febrile, toxic stages and at follow-up were analysed for HGF. Serum samples obtained from nine healthy children served as the control group. RESULTS In dengue-infected patients, serum HGF was significantly higher at the febrile and toxic stages than at follow-up (p<0.05). In comparison with DF, patients with DHF had a greater level of HGF at the febrile stage (p<0.05). A cut-off HGF level of 1220 pg/mL obtained during the febrile stage showed a sensitivity of 90% and a specificity of 53% for predicting clinical progression to DHF (area under the ROC curve 0.75). CONCLUSION Serum HGF level at the early stage of dengue virus infection is elevated and may be a useful predictor for clinical progression to DHF.
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Affiliation(s)
- N Voraphani
- Department of Paediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Abstract
Hepatocyte growth factor (HGF), originally purified from the plasma of patients with fulminant hepatic failure, has been shown to carry out various physiological functions. HGF not only stimulates liver regeneration, but also acts as an antiapoptotic factor in in vivo experimental models. Therefore, HGF is a promising therapeutic agent for the treatment of fatal liver diseases, including fulminant hepatic failure. After performing a number of preclinical tests, our group began an investigator-initiated registered phase I/II clinical trial of patients with fulminant hepatic failure to examine the safety and clinical efficacy of recombinant human HGF. In this article, we will discuss the basic research results as well as the translational research that underpins current attempts to use HGF in various clinical settings.
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Affiliation(s)
- Akio Ido
- Department of Digestive and Life-style Related Disease, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima, Japan
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22
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Ohtaka K, Machida S, Ohzeki T, Tanaka M, Kurosaka D, Masuda T, Ishii T. Protective Effect of Hepatocyte Growth Factor Against Degeneration of the Retinal Pigment Epithelium and Photoreceptor in Sodium Iodate–Injected Rats. Curr Eye Res 2009; 31:347-55. [PMID: 16603468 DOI: 10.1080/02713680600629797] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
PURPOSE To investigate the possible protective effect of hepatocyte growth factor (HGF) against degeneration of photoreceptors and retinal pigment epithelium (RPE) in vivo. METHODS Sprague-Dawley (SD) rats received an intravitreal injection of HGF in the right eye. The left eye was injected with vehicle as a control. Two days after the intravitreal injections, rats were administered 40 mg/kg of sodium iodate (NaIO3) intravenously. Scotopic ERGs were elicited by different stimulus intensities with a maximum luminance of 0.84 log cds/m2. To evaluate RPE function, the azide response was evoked by intravenous injection of 0.1 mg sodium azide. These electrophysiological measurements were conducted on days 4, 7, 14, and 28 after the NaIO3 injections. After recording ERGs or azide response, animals were sacrificed for quantification of the histological change and immunohistochemical analysis using antibodies against RPE 65. RESULTS The threshold for the scotopic b-wave was significantly lower in HGF-treated eyes than in untreated control eyes (p < 0.005), and maximum b-wave amplitudes (Vbmax) were significantly larger in HGF-treated eyes (p < 0.05) across all experimental time points after NaIO3 injection. Azide response amplitudes were significantly larger in the HGF-treated eyes than in the untreated eyes (p < 0.05). The structure of the outer retina was preserved to a greater degree in the HGF-treated eyes than in the untreated eyes (p < 0.05). Immunohistochemical analysis demonstrated that irregular alignment of the outer nuclear layer was confined to the retinal area that was not stained with RPE 65. CONCLUSIONS Our results indicated that an intravitreal injection of HGF provided significant protection against degeneration of the photoreceptor and RPE induced by systemic administration of NaIO3. This suggests that HGF could be used as a therapeutic agent for degeneration of photoreceptors as well as RPE.
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Affiliation(s)
- Kouji Ohtaka
- Department of Ophthalmology, Iwate Medical University School of Medicine, Iwate, Japan
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Yu CH, Chen HL, Chen YH, Chang MF, Chien CS, Chang MH. Impaired hepatocyte regeneration in acute severe hepatic injury enhances effective repopulation by transplanted hepatocytes. Cell Transplant 2009; 18:1081-92. [PMID: 19650970 DOI: 10.3727/096368909x12483162196647] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Efficient repopulation by transplanted hepatocytes in the severely injured liver is essential for their clinical application in the treatment of acute hepatic failure. We studied here whether and how the transplanted hepatocytes are able to efficiently repopulate the toxin-induced acute injured liver. Male dipeptidyl peptidase IV-deficient F344 rats were randomized to receive retrorsine plus D-galactosamine (R+D-gal) treatment or D-galactosamine-alone (D-gal) to induce acute hepatic injury, and retrorsine-alone. In these models, retrorsine was used to inhibit the proliferation of endogenous hepatocytes while D-galactosamine induced acute hepatocyte damage. Wild-type hepatocytes (1 x 10(7)/ml) were transplanted intraportally 24 h after D-galactosamine or saline injection. The kinetics of proliferation and repopulation of transplanted cells and the kinetics of cytokine response, hepatic stellate cell (HSC) activation, and matrix metalloproteinase (MMP2) expression were analyzed. We observed that early entry of transplanted hepatocytes into the hepatic plates and massive repopulation of the liver by transplanted hepatocytes occurred in acute hepatic injury induced by R+D-gal treatment but not by D-gal-alone or retrorsine-alone. The expressions of transforming growth factor-alpha and hepatocyte growth factor genes in the R+D-gal injured liver were significantly upregulated and prolonged up to 4 weeks after hepatocyte transplantation. The expression kinetics were parallel with the efficient proliferation and repopulation of transplanted hepatocytes. HSC was activated rapidly, markedly, and prolongedly up to 4 weeks after hepatocyte transplantation, when the expression of HGF gene and repopulation of transplanted hepatocytes were reduced afterward. Furthermore, the expression kinetics of MMP2 and its specific distribution in the host areas surrounding the expanding clusters of transplanted hepatocytes are consistent with those of activated HSC. Impaired hepatocyte regeneration after acute severe hepatic injury may initiate serial compensatory repair mechanisms that facilitate the extensive repopulation by transplanted hepatocytes that enter early the hepatic plates.
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Affiliation(s)
- Chun-Hsien Yu
- Graduate Institute of Clinical Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
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Ono T, Tsuji T, Sakai M, Yukizaki C, Ino H, Akagi I, Hiramatsu K, Matsumoto Y, Sugiura Y, Uto H, Tsubouchi H, Gohda E. Induction of hepatocyte growth factor production in human dermal fibroblasts and their proliferation by the extract of bitter melon pulp. Cytokine 2009; 46:119-26. [DOI: 10.1016/j.cyto.2008.12.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2008] [Revised: 12/12/2008] [Accepted: 12/29/2008] [Indexed: 10/21/2022]
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Fukuta K, Adachi E, Matsumoto K, Nakamura T. Different reactivities of enzyme-linked immunosorbent assays for hepatocyte growth factor. Clin Chim Acta 2009; 402:42-6. [DOI: 10.1016/j.cca.2008.12.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2008] [Revised: 12/05/2008] [Accepted: 12/08/2008] [Indexed: 10/21/2022]
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Anan F, Masaki T, Yonemochi H, Takahashi N, Nakagawa M, Eshima N, Saikawa T, Yoshimatsu H. Hepatocyte growth factor levels are associated with the results of 123I-metaiodobenzylguanidine myocardial scintigraphy in patients with type 2 diabetes mellitus. Metabolism 2009; 58:167-73. [PMID: 19154948 DOI: 10.1016/j.metabol.2008.09.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2008] [Accepted: 09/11/2008] [Indexed: 11/24/2022]
Abstract
Elevated hepatocyte growth factor (HGF) levels and cardiovascular autonomic dysfunction are associated with a high mortality rate in patients with type 2 diabetes mellitus. We tested the hypothesis that elevated HGF is associated with insulin resistance and cardiovascular autonomic dysfunction in patients with type 2 diabetes mellitus not receiving insulin treatment. The study group consisted of 21 type 2 diabetes mellitus patients with high HGF levels (>0.26 ng/mL, 58 +/- 5 years old, high-HGF group). The control group consisted of 25 type 2 diabetes mellitus patients with normal HGF levels (<or=0.26 ng/mL, 58 +/- 9 years old, normal-HGF group). Cardiovascular autonomic function was assessed by baroreflex sensitivity, heart rate variability, plasma norepinephrine concentrations, and cardiac (123)I-metaiodobenzylguanidine (MIBG) scintigraphy. Early and delayed (123)I-MIBG myocardial uptake values were lower (P < .005 and P < .01, respectively) and the percentage of washout rate of (123)I-MIBG was higher (P < .001) in the high-HGF group than in the normal-HGF group. The fasting plasma insulin concentrations (P < .0001) and the homeostasis model assessment index values (P < .0001) were higher in the high-HGF group than in the normal-HGF group. Multiple regression analysis revealed that the level of HGF was independently predicted by the homeostasis model assessment index values and the myocardial uptake of (123)I-MIBG at the delayed phase. Our results demonstrate that high levels of HGF are associated with depressed cardiovascular autonomic function and insulin resistance in patients with type 2 diabetes mellitus.
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Affiliation(s)
- Futoshi Anan
- Department of Cardiology, Oita Red Cross Hospital, Oita 870-0033, Japan.
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Motoki T, Sugiura Y, Matsumoto Y, Tsuji T, Kubota S, Takigawa M, Gohda E. Induction of hepatocyte growth factor expression by maleic acid in human fibroblasts through MAPK activation. J Cell Biochem 2008; 104:1465-76. [DOI: 10.1002/jcb.21724] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Matsumoto Y, Motoki T, Kubota S, Takigawa M, Tsubouchi H, Gohda E. Inhibition of tumor-stromal interaction through HGF/Met signaling by valproic acid. Biochem Biophys Res Commun 2007; 366:110-6. [PMID: 18053801 DOI: 10.1016/j.bbrc.2007.11.089] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2007] [Accepted: 11/19/2007] [Indexed: 11/18/2022]
Abstract
Hepatocyte growth factor (HGF), which is produced by surrounding stromal cells, including fibroblasts and endothelial cells, has been shown to be a significant factor responsible for cancer cell invasion mediated by tumor-stromal interactions. We found in this study that the anti-tumor agent valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, strongly inhibited tumor-stromal interaction. VPA inhibited HGF production in fibroblasts induced by epidermal growth factor (EGF), platelet-derived growth factor, basic fibroblast growth factor, phorbol 12-myristate 13-acetate (PMA) and prostaglandin E(2) without any appreciable cytotoxic effect. Other HDAC inhibitors, including butyric acid and trichostatin A (TSA), showed similar inhibitory effects on HGF production stimulated by various inducers. Up-regulations of HGF gene expression induced by PMA and EGF were also suppressed by VPA and TSA. Furthermore, VPA significantly inhibited HGF-induced invasion of HepG2 hepatocellular carcinoma cells. VPA, however, did not affect the increases in phosphorylation of MAPK and Akt in HGF-treated HepG2 cells. These results demonstrated that VPA inhibited two critical processes of tumor-stromal interaction, induction of fibroblastic HGF production and HGF-induced invasion of HepG2 cells, and suggest that those activities serve for other anti-tumor mechanisms of VPA besides causing proliferation arrest, differentiation, and/or apoptosis of tumor cells.
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Affiliation(s)
- Yohsuke Matsumoto
- Department of Immunochemistry, Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 1-1-1, Tsushima-naka, Okayama 700-8530, Japan
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Anan F, Shimomura T, Imagawa M, Masaki T, Nawata T, Takahashi N, Yonemochi H, Eshima N, Saikawa T, Yoshimatsu H. Predictors for silent cerebral infarction in patients with chronic renal failure undergoing hemodialysis. Metabolism 2007; 56:593-8. [PMID: 17445532 DOI: 10.1016/j.metabol.2007.01.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2006] [Accepted: 12/23/2006] [Indexed: 11/18/2022]
Abstract
In patients with chronic renal failure undergoing hemodialysis (HD), silent cerebral infarctions (SCIs) are associated with high mortality. Levels of hepatocyte growth factor (HGF) increase with renal dysfunction and may be a novel predictor of cerebrovascular events. We examined if HGF is a predictor of SCI in HD patients. Brain magnetic resonance imaging findings were used to divide 50 patients undergoing HD into 2 groups, a group with SCI (age, 61 +/- 8 years, mean +/- SD; n = 27) and a group without SCI (age, 60 +/- 7 years; n = 23). These patients received 24-hour ambulatory blood pressure monitoring. The number of patients with diabetes or hypertension was not different between the 2 groups. We made the following observations: (1) The percentage of smokers was higher in the group with SCI than in the group without SCI (P < .05). (2) Plasma levels of high-density lipoprotein cholesterol were lower and HGF levels were higher in the group with SCI compared with the group without SCI (P < .05 and P < .005, respectively). (3) Systolic ambulatory blood pressure and mean heart rate at night were higher in the group with SCI than in the group without SCI (P < .05). Multiple logistic regression analysis identified HGF as a significant risk factor for SCI (odds ratio, 1.89; 95% confidence interval, 1.57-3.38; P < .005). Our findings indicate that HGF may be a novel useful predictor of SCI in patients with chronic renal failure undergoing HD.
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Affiliation(s)
- Futoshi Anan
- Department of Cardiology, Oita Red Cross Hospital, Oita, Japan.
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Auth MKH. Are hepatic growth factors predictors of clinical outcome in fulminant hepatic failure? J Pediatr Gastroenterol Nutr 2007; 44:168-70. [PMID: 17255826 DOI: 10.1097/mpg.0b013e31802c9379] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Katano H, Kamiya K, Mase M, Tanikawa M, Yamada K. Tissue plasminogen activator in chronic subdural hematomas as a predictor of recurrence. J Neurosurg 2006; 104:79-84. [PMID: 16509150 DOI: 10.3171/jns.2006.104.1.79] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Object
Chronic subdural hematomas (CSDHs) recur in 7 to 18% of cases. The present study was conducted to determine whether serum or lesion concentrations of coagulofibrinolytic and angiogenic factors, which have been reported to be potential markers of CSDH development, might predict such recurrences.
Methods
Sixty consecutive patients (mean age 71.5 years) with CSDHs (74 affected sides) were studied. Samples of serum in preoperative peripheral venous blood and of hematomas (obtained during surgery) were collected and analyzed. The CSDH recurred in six (8.1%) of the 74 affected sides in six patients. None of the values of the coagulative factors or tests in serum showed significant variation between cases with and those without recurrence. Among coagulofibrinolytic factors, tissue plasminogen activator (TPA) in hematomas demonstrated significantly greater levels in recurrent than in nonrecurrent cases; a similar tendency was noted for α2-plasmin inhibitor–plasmin complex in hematomas. Both factors were greater in the lesions than in the serum. Among the angiogenic factors, levels of hepatic growth factor (HGF) and vascular endothelial growth factor (VEGF) in hematomas were significantly greater than in serum, whereas those of basic fibroblast growth factor were rather lower. Note that comparisons between recurrent and nonrecurrent cases revealed no significant difference.
Conclusions
Patients harboring CSDHs with high TPA concentrations on sampling at the initial surgery have a relatively high probability of recurrence and require follow up with computerized tomography scanning. Angiogenic factors, such as HGF and VEGF, might be candidate markers of CSDH enlargement but are not useful as predictors of recurrence.
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Affiliation(s)
- Hiroyuki Katano
- Department of Neurosurgery and Restorative Neuroscience, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
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Takami Y, Yamamoto I, Tsubouchi H, Gohda E. Modulation of hepatocyte growth factor induction in human skin fibroblasts by retinoic acid. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2005; 1743:49-56. [PMID: 15777839 DOI: 10.1016/j.bbamcr.2004.08.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2003] [Revised: 06/28/2004] [Accepted: 08/13/2004] [Indexed: 10/26/2022]
Abstract
Topical treatment of skin with all-trans-retinoic acid (ATRA), the major biologically active form of vitamin A, results in hyperproliferation of basal keratinocytes, leading to an accelerated turnover of epidermis cells and thickening of the epidermis, probably via induction of production of paracrine growth factors for keratinocytes in epidermal suprabasal keratinocytes and/or dermal fibroblasts. Since hepatocyte growth factor (HGF) is a factor mitogenic to epidermal keratinocytes secreted from dermal fibroblasts, the effect of ATRA on basal and induced HGF production in human dermal fibroblasts in culture was examined. ATRA alone did not induce HGF production, but it significantly enhanced HGF production induced by the cAMP-elevating agent cholera toxin or the membrane-permeable cAMP analog 8-bromo-cAMP. Cholera toxin-induced activation of cAMP responsive element (CRE)-binding protein (CREB) was enhanced by pretreating cells with ATRA for 24 h. In contrast, HGF production induced by epidermal growth factor (EGF) or phorbol 12-myristate 13-acetate (PMA) was potently inhibited by ATRA. These modulatory effects of ATRA were different from the effects of transforming growth factor-beta1 (TGF-beta) and dexamethasone, both of which inhibited HGF production induced by all of the four inducers. Up-regulation of HGF gene expression by cholera toxin and EGF was also enhanced and inhibited, respectively, by ATRA. Both 9-cis-retinoic acid (9-cis-RA) and 13-cis-retinoic acid (13-cis-RA), which are stereo-isomers of ATRA, showed a modulatory effect on HGF induction similar to that of ATRA. These results suggest that ATRA augments the induction of HGF production caused by increased intracellular cAMP.
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Affiliation(s)
- Yoichiro Takami
- Department of Immunochemistry, Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka, Okayama 700-8530, Japan
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Auth MKH, Boost KA, Leckel K, Beecken WD, Engl T, Jonas D, Oppermann E, Hilgard P, Markus BH, Bechstein WO, Blaheta RA. Controlled and reversible induction of differentiation and activation of adult human hepatocytes by a biphasic culture technique. World J Gastroenterol 2005; 11:2080-7. [PMID: 15810072 PMCID: PMC4305775 DOI: 10.3748/wjg.v11.i14.2080] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Clinical application of human hepatocytes (HC) is hampered by the progressive loss of growth and differentiation in vitro. The object of the study was to evaluate the effect of a biphasic culture technique on expression and activation of growth factor receptors and differentiation of human adult HC.
METHODS: Isolated HC were sequentially cultured in a hormone enriched differentiation medium (DM) containing nicotinamide, insulin, transferrin, selenium, and dexame-thasone or activation medium (AM) containing hepatocyte growth factor (HGF), epidermal growth factor (EGF), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Expression, distribution and activation of the HC receptors (MET and EGFR) and the pattern of characteristic cytokeratin (CK) filaments were measured by fluorometry, confocal microscopy and Western blotting.
RESULTS: In the biphasic culture system, HC underwent repeated cycles of activation (characterized by expression and activation of growth factor receptors) and re-differentiation (illustrated by distribution of typical filaments CK-18 but low or absent expression of CK-19). In AM increased expression of MET and EGFR was associated with receptor translocation into the cytoplasm and induction of atypical CK-19. In DM low expression of MET and EGFR was localized on the cell membrane and CK-19 was reduced. Receptor phosphorylation required embedding of HC in collagen type I gel.
CONCLUSION: Control and reversible modulation of growth factor receptor activation of mature human HC can be accomplished in vitro, when defined signals from the extracellular matrix and sequential growth stimuli are provided. The biphasic technique helps overcome de-differentiation, which occurs during continuous stimulation by means of growth factors.
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Affiliation(s)
- Marcus-K H Auth
- Universitäts-Kinderklinik Essen,Abteilung für Allgemeine Pädiatrie, Germany.
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Takami Y, Motoki T, Yamamoto I, Gohda E. Synergistic induction of hepatocyte growth factor in human skin fibroblasts by the inflammatory cytokines interleukin-1 and interferon-γ. Biochem Biophys Res Commun 2005; 327:212-7. [PMID: 15629451 DOI: 10.1016/j.bbrc.2004.11.144] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2004] [Indexed: 11/29/2022]
Abstract
Hepatocyte growth factor (HGF) is one of the vital factors for wound healing. HGF expression markedly increases in wounded skin and is mainly localized in dermal fibroblasts. HGF expression level in human dermal fibroblasts in vitro, however, is low and thus may be stimulated by some factors in the process of wound healing. Candidates of the factors are inflammatory cytokines released by polymorphonuclear and mononuclear cells infiltrating the wounded area, but HGF production in human dermal fibroblasts is only slightly induced by interleukin (IL)-1, tumor necrosis factor (TNF)-alpha or interferon (IFN)-gamma. We here report that a combination of IL-1beta and IFN-gamma or a combination of TNF-alpha and IFN-gamma very markedly induced HGF production. The synergistic effect of the former was more marked than that of the latter. Synergistic effects of IL-1beta and IFN-gamma were observed at more than 10 pg/ml and 10 IU/ml, respectively, and were detectable as early as 12 h after addition. Neither IFN-alpha nor IFN-beta was able to replace IFN-gamma. HGF mRNA expression was also synergistically upregulated by IL-1beta and IFN-gamma. IL-1beta plus IFN-gamma-induced synergistic production of HGF was potently inhibited by treatment of cells with the extracellular signal-regulated kinase (ERK) kinase inhibitor PD98059 and the p38 inhibitor SB203580 but not by the c-Jun N-terminal kinase (JNK) inhibitor SP600125. Taken together, our results indicate that a combination of IL-1beta and IFN-gamma synergistically induced HGF production in human dermal fibroblasts and suggest that activation of ERK and p38 but not of JNK is involved in the synergistic effect.
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Affiliation(s)
- Yoichiro Takami
- Department of Immunochemistry, Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka, Okayama 700-8530, Japan
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Yagi S, Iida T, Taniguchi K, Hori T, Hamada T, Fujii K, Mizuno S, Uemoto S. Impact of portal venous pressure on regeneration and graft damage after living-donor liver transplantation. Liver Transpl 2005; 11:68-75. [PMID: 15690538 DOI: 10.1002/lt.20317] [Citation(s) in RCA: 123] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Several reports claim that portal hypertension after living-donor liver transplantation (LDLT) adversely affects graft function, but few have assessed the impact of portal venous pressure (PVP) on graft regeneration. We divided 32 adult LDLT recipients based on mean PVP during the 1st 3 days after LDLT into a group with a PVP > or = 20 mm of Hg (H Group; n = 17), and a group with a PVP < 20 mm of Hg (L Group; n = 15). Outcome in the H Group was poorer than in the L Group (58.8 vs. 92.9% at 1 year). Peak peripheral hepatocyte growth factor (HGF) during the 1st 2 weeks was higher in the H Group (L: 1,730 pg/mL, H: 3,696 pg/mL; P < .01), whereas peak portal vascular endothelial growth factor (VEGF) level during the 1st week was higher in the L Group (L: 433 pg/mL, H: 92 pg/mL; P < .05). Graft volume (GV) / standard liver volume (SLV) was higher in the H Group (L / H, at 2, 3, and 4 weeks, and at 3 months: 1.02 / 1.24, .916 / 1.16, .98 / 1.27, and .94 / 1.29, respectively; P < .05). Peak serum aspartate aminotransferase, bilirubin levels, and international normalized ratio after LDLT were significantly higher in the H Group, as was mean ascitic fluid volume. In conclusion, early postoperative PVP elevation to 20 mm of Hg or more was associated with rapid graft hypertrophy, higher peripheral blood HGF levels, and lower portal VEGF levels; and with a poor outcome, graft dysfunction with hyperbilirubinemia, coagulopathy, and severe ascites. Adequate liver regeneration requires an adequate increase in portal venous pressure and flow reflected by clearance of HGF and elevated VEGF levels.
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Affiliation(s)
- Shintaro Yagi
- First Department of Surgery, Mie University School of Medicine, 2-174, Edobashi, Tsu City, Mie Prefecture, 514-8507, Japan.
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Takami Y, Kanasaki K, Tsubouchi H, Ishii T, Yamamoto I, Gohda E. Inhibition of hepatocyte growth factor induction in human dermal fibroblasts by interleukin-1 and its prevention by interferon-γ. Biochem Biophys Res Commun 2004; 325:676-82. [PMID: 15541342 DOI: 10.1016/j.bbrc.2004.10.093] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2004] [Indexed: 11/19/2022]
Abstract
Hepatocyte growth factor (HGF) is one of the vital factors for liver regeneration. HGF production is induced by the activation of protein kinase A and protein kinase C-mediated pathways, interleukin (IL)-1, tumor necrosis factor (TNF)-alpha, and epidermal growth factor (EGF) in mesenchymal cells. We here report that IL-1 and TNF-alpha, hitherto regarded as HGF inducers, potently inhibited HGF production stimulated by other HGF inducers. IL-1alpha, IL-1beta, and TNF-alpha alone had minimal stimulating effects on HGF production in human dermal fibroblasts, but they strongly inhibited production of HGF induced by cholera toxin, 8-bromo-cAMP, EGF, and phorbol 12-myristate 13-acetate (PMA). Moreover, although the high level of HGF production in MRC-5 cells was enhanced by PMA and less markedly by IL-1beta, HGF production in MRC-5 cells treated with PMA plus IL-1beta was less than that in the cells treated with PMA alone. In the presence of interferon (IFN)-gamma, however, cholera toxin- and 8-bromo-cAMP-induced HGF production was not inhibited by IL-1beta. Pretreatment of cells with IL-1beta suppressed the phosphorylation of cAMP-responsive element-binding protein induced by cholera toxin but not that induced by 8-bromo-cAMP. Taken together, our results indicate that IL-1 inhibited HGF production stimulated by various inducers, including protein kinase A-activating agents, and that IFN-gamma overcame this inhibition of induction of HGF production.
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Affiliation(s)
- Yoichiro Takami
- Department of Immunochemistry, Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka, Okayama 700-8530, Japan
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Ozden M, Kalkan A, Demirdag K, Denk A, Kilic SS. Hepatocyte growth factor (HGF) in patients with hepatitis B and meningitis. J Infect 2004; 49:229-35. [PMID: 15337340 DOI: 10.1016/j.jinf.2003.12.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/04/2003] [Indexed: 12/22/2022]
Abstract
OBJECTIVES The present study investigates serum hepatocyte growth factor (HGF) levels in patients with acute and chronic hepatitis B and the relation between these levels and intrahepatic inflammatory markers of the liver and fibrosis, as well as the cerebrospinal fluid (CSF) HGF levels in patients with meningitis and the relation between these levels and CSF findings. To our knowledge this is the first study regarding CSF HGF levels in tuberculous meningitis. PATIENTS AND METHODS The study consisted of 35 patients with chronic hepatitis B (HbeAg and HBV-DNA positive), 20 with acute hepatitis B, 20 with acute bacterial meningitis and 15 having tuberculous meningitis. HGF levels in the serum and CSF samples were measured by using the ELISA method. RESULTS The mean serum HGF levels in acute hepatitis B group were found statistically significantly higher than those in the control group and chronic hepatitis B group (p<0.0001). It was established that serum HGF levels in patients with chronic hepatitis B were significantly correlated with serum alanine aminotransferase (ALT) and HBV-DNA levels (r: 0.816, 0.951; p<0.05, respectively). Similarly, serum HGF levels of patients with chronic hepatitis B were correlated with fibrosis score and hepatic activity index of the liver histopathology (r: 0.750, 0.459; p<0.05, respectively). The mean CSF HGF levels of patients with acute bacterial meningitis and tuberculous meningitis were higher than those in the control group (p<0.05). In addition, it was observed that mean CSF HGF levels in patients suffered from tuberculous meningitis were statistically significantly higher than those in acute bacterial meningitis (p<0.05). CONCLUSIONS We suggest that serum HGF level in patients with chronic hepatitis B might reflect viral load, necro-inflammatory activity in the liver and the degree of structural progression. Our findings have demonstrated that tuberculous meningitis cause increased HGF concentrations in CSF. It is, therefore, suggested that examination of HGF levels in CSF may provide additional information in the differential diagnosis.
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Affiliation(s)
- M Ozden
- Department of Immunology, Faculty of Medicine, University of Firat, TR-23119 Elazig, Turkey.
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Ito Y, Eguchi S, Kamohara Y, Inuo H, Yamanouchi K, Okudaira S, Yanaga K, Furui J, Kanematsu T. Influence of serum from rats with fulminant hepatic failure on hepatocytes in a bioartificial liver system. Int J Artif Organs 2004; 27:303-10. [PMID: 15163064 DOI: 10.1177/039139880402700406] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Fulminant hepatic failure (FHF) is a life-threatening condition marked by many excessively increased unmetabolized toxins and growth factors. Recently developed bioartificial liver (BAL) systems containing hepatocytes can be used to treat patients with FHF However, the behavior of these hepatocytes on exposure to FHF serum in vitro remains unclear. In the present study, we used FHF rat models and the sera from these rats (i.e., FHF serum) contained elevated inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6), HGF, and TGF-beta1. In addition, 1x10(8) hepatocytes were harvested from the livers of inbred rats and incubated with microcarrier beads. Four hours later, the hepatocyte-coated beads were inoculated into a hollow-fiber module (=BAL system). FHF serum or normal control serum circulated for 6 hours through the BAL system. Expressions of mRNA for albumin, GST A1, CYP 1A2, OTC and c-fos were investigated by RT-PCR, and PCNA staining was performed before and after perfusion. The expressions of albumin, GST A1, and CYP 1A2 mRNAs were markedly decreased, whereas those of OTC and c-fos were modestly decreased. PCNA positive cells were low and showed no difference between FHF and normal serum-exposed hepatocytes. In conclusion, the exposure of hepatocytes to hypercytokinemia, including inflammatory cytokines and positive and negative growth factors, caused a loss in liver specific functions. This environment also failed to facilitate hepatocyte regeneration.
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Affiliation(s)
- Y Ito
- Department of Transplantation and Digestive Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
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Vejchapipat P, Theamboonlers A, Chaokhonchai R, Chongsrisawat V, Chittmittrapap S, Poovorawan Y. Serum hepatocyte growth factor and clinical outcome in biliary atresia. J Pediatr Surg 2004; 39:1045-1049. [PMID: 15213896 DOI: 10.1016/j.jpedsurg.2004.03.052] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE Biliary atresia (BA) remains one of the most intractable liver diseases leading to liver fibrosis. Serum hepatocyte growth factor (HGF) has been shown to increase in cirrhotic patients. The aim of this study was to investigate the possible role of HGF in BA. METHODS Serum levels of HGF were determined using an enzyme-linked immunosorbent assay from 28 BA patients and 25 healthy children. The patients were categorized into 3 groups according to their clinical outcomes (good, fair, and poor): group A (good), jaundice-free patients (total bilirubin [TB] < 2.0 mg%); group B (fair), patients with mild to moderate jaundice (TB, 2 to 10 mg%); and group C (poor), patients with marked jaundice (TB > 10 mg%). Unpaired t test and analysis of variance (ANOVA) with post-hoc tests were used. Data were expressed as mean and SEM. RESULTS Serum HGF levels in BA patients were higher than the controls (P =.02). Subgroup analysis found that there were 12 patients in group A, 8 patients in group B, and 8 patients in group C. The mean age of patients in groups A, B, and C were 5.34 +/- 0.52, 7.45 +/- 1.98, and 5.49 +/- 1.57 years (P >.05). Serum HGF in controls and groups A, B, and C were 0.24 +/- 0.03, 0.28 +/- 0.04, 0.36 +/- 0.09, and 0.56 +/- 0.07 ng/mL, respectively. Serum HGF levels in BA patients with poor outcome were higher than patients with good outcome (P =.02). There was no difference in serum HGF of BA patients with fair outcome compared with other groups. CONCLUSIONS Serum HGF is elevated in BA. Furthermore, BA patients with poor outcome have significantly elevated HGF compared with patients with good outcome. Serum HGF levels may be predictive of prognosis with respect to the progression of liver dysfunction. However, the results of HGF in patients with fair outcome are inconclusive, probably because of the small sample size. Further studies are needed to elucidate the detailed mechanisms.
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Affiliation(s)
- Paisarn Vejchapipat
- Department of Surgery, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Abstract
BACKGROUND Graft rejection is a major complication of lung transplantation. No serological marker of rejection is in common use. Hepatocyte growth factor (HGF) is highly expressed in the lung and produced after acute lung injury; serum concentrations increase in inflammatory lung diseases. We investigated whether HGF could be an accurate marker for prediction of lung-graft rejection. METHODS Serum concentrations of HGF were measured by ELISA in 109 patients who had undergone lung transplantation (65 for chronic obstructive pulmonary disease; 23 for cystic fibrosis; 21 for idiopathic lung fibrosis), comparing those who had no subsequent events and those with episodes of infection or rejection, as well as in 12 healthy controls. FINDINGS The mean baseline serum HGF concentration was 645 ng/L (SD 259) in controls and 1358 ng/L (603) in the patients before transplantation. After transplantation the mean concentration in patients with no events was 1147 ng/L (510) compared with 1559 ng/L (323) in patients with infection (p=0.001 vs controls; change from pretransplant value not significant). Patients with rejection had significantly higher concentrations than all other groups (3972 ng/L [1463], p<0.0001). Logistic regression identified HGF as a predictor for lung graft rejection (p=0.012). After steroid treatment, HGF concentrations returned almost to the preoperative values within 3 days. INTERPRETATION HGF might be a marker for graft rejection in lung transplantation. A potential link between viral infection, mainly cytomegalovirus, and HGF, however, remains to be investigated.
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Affiliation(s)
- Seyedhossein Aharinejad
- Laboratory for Cardiovascular Research, Department of Anatomy, Medical University of Vienna, Vienna, Austria.
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Ohnishi T, Daikuhara Y. Hepatocyte growth factor/scatter factor in development, inflammation and carcinogenesis: its expression and role in oral tissues. Arch Oral Biol 2004; 48:797-804. [PMID: 14596869 DOI: 10.1016/s0003-9969(03)00180-8] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Hepatocyte growth factor (HGF) was discovered as a potent mitogen for adult hepatocytes from the plasma of patients with fulminant hepatic failure. It is now known to be a broad-spectrum, multi-functional mitogen, motogen and morphogen. The activities of HGF are mediated through the signalling pathway of its receptor, c-Met. During tooth development, HGF is expressed in the dental papilla and c-Met is expressed in the inner enamel epithelium. The expression of HGF and c-Met indicates that HGF is involved in morphogenesis of the tooth by mediating epithelial-mesenchymal interactions. In the mature tooth, HGF expression by fibroblasts is enhanced in pulpitis and mediated through the induction of prostaglandin (PG) E(2); it is induced not only by inflammatory cytokines, but also by components of oral bacteria. Consequently, concentrations of HGF in gingival crevicular fluid (GCF) increase in periodontitis. The mitogenic and other biological activities, such as angiogenesis, of HGF contribute towards wound healing. Both HGF and c-Met are expressed in the developing tongue, and the signalling pathway of the latter is shown to be essential for myogenesis. Dysregulation of c-Met signalling is observed in carcinogenesis, but HGF also has cytotoxic activity to certain tumour cells. The reason for the discrepancy between these observations is not clear at present.
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Affiliation(s)
- Tomokazu Ohnishi
- Department of Biochemistry, Kagoshima University Dental School, 35-1 Sakuragaoka-8, 890, Kagoshima, Japan
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Nozato E, Shiraishi M, Nishimaki T. Up-regulation of hepatocyte growth factor caused by an over-expression of transforming growth factor beta, in the rat model of fulminant hepatic failure. J Surg Res 2004; 115:226-34. [PMID: 14697288 DOI: 10.1016/s0022-4804(03)00316-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND The role of transforming growth factor beta (TGF-beta), a potent regulator of cellular growth, was investigated in the rat model of fulminant hepatic failure (FHF). MATERIALS AND METHODS The rat FHF model was created by a combination of a 68% partial hepatectomy (PH) and 7% of necrosis (each n = 25 in Groups 1, 2 and 3). Adenovirus mediated gene transfer of mature human TGF-beta1 gene was performed by the systemic injection of AxCAhTGFb1 (1 x 10(9) pfu) in Group 1, 3 days before FHF. In control Groups 2 and 3, recombinant lacZ adenovirus (AxCAlacZ, Group 2) and normal saline (1 ml, Group 3) were used, instead of AxCAhTGFb1. RESULTS An excessive expression of TGF-beta1 in Group 1 resulted in an inhibition of hepatocyte proliferation (24-48 h after FHF) and gaining of liver weight (24-48 h), increased expression of HGF in liver tissue (24 h), and decreased expression of TGF-alpha (24 h), compared to those in control Groups 2 and 3. Serum IL-6 levels were also elevated by a TGF-beta1 over-expression at 24 hrs after FHF in Group 1. CONCLUSIONS The forced expression of TGF-beta1 in the FHF liver yields both a secondary increase of HGF production and a suppression of liver regeneration, which might explain the mechanism of increased serum HGF observed in a clinical FHF. TGF-beta1 is thus thought to have an important role in inhibiting liver regeneration after FHF.
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Affiliation(s)
- Eiji Nozato
- First Department of Surgery, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
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Yagi Y, Sotani T, Nagao T, Horio T, Yamamoto I, Gohda E. Induction by staurosporine of hepatocyte growth factor production in human skin fibroblasts independent of protein kinase inhibition. Biochem Pharmacol 2003; 66:1797-808. [PMID: 14563490 DOI: 10.1016/s0006-2952(03)00547-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Staurosporine is one of the most potent and well known inhibitors of protein kinases, and it is often used to study the involvement of protein kinases in signal transduction pathways. We now report that staurosporine can induce the production of hepatocyte growth factor (HGF) independently of protein kinase inhibition. Staurosporine markedly stimulated the production of HGF in various cell types, including human skin fibroblasts. Its effect was accompanied by up-regulation of HGF gene expression. The inhibition of protein kinases appears not to be involved in staurosporine-induced HGF production, because other protein kinase inhibitors, K-252a, H-7, GF 109203X and genistein, had no HGF-inducing activity. UCN-01, 7-hydroxystaurosporine, which differs from staurosporine only in its aglycone moiety, also showed HGF-inducing activity, and inactive K-252a differs from staurosporine only in its sugar moiety. These results indicate that the sugar moiety, a six-atom ring structure, is important in the HGF-inducing activity of staurosporine. Experiments were then carried out to determine whether the characteristics of staurosporine-induced HGF production have similarities to those of HGF production stimulated by other HGF inducers. The effect of staurosporine like that of 8-bromo-cAMP and that of cholera toxin was marked in human skin fibroblasts from all four different sources, whereas the effects of epidermal growth factor and phorbol 12-myristate 13-acetate were variable depending on cells. The net increase in HGF production induced by staurosporine was not reduced in protein kinase C-depleted human skin fibroblasts. Moreover, synergistic induction of HGF was detected between staurosporine and interferon-gamma as well as between 8-bromo-cAMP and interferon-gamma. Staurosporine, however, did not increase intracellular cAMP levels in human skin fibroblasts. These results indicate that staurosporine induced HGF in different cell types via a signaling pathway similar to the cAMP-mediated pathway without increasing cAMP levels.
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Affiliation(s)
- Yasuyuki Yagi
- Department of Immunochemistry, Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka, Okayama 700-8530, Japan
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Affiliation(s)
- Leonidas G Koniaris
- Department of Surgery, University of Rochester School of Medicine, Rochester, NY, USA
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Tsuboi Y, Kakimoto K, Nakajima M, Akatsu H, Yamamoto T, Ogawa K, Ohnishi T, Daikuhara Y, Yamada T. Increased hepatocyte growth factor level in cerebrospinal fluid in Alzheimer's disease. Acta Neurol Scand 2003; 107:81-6. [PMID: 12580855 DOI: 10.1034/j.1600-0404.2003.02089.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND & OBJECTIVE Hepatocyte growth factor (HGF), also known as the scatter factor, is a potent mitogen for mature hepatocytes, and also has multifunctional effects on some cells in various organs. Recently, we have found expression and localization of HGF in white matter astrocytes in human brain tissues. Furthermore, immunohistochemistry using anti-HGF antibody revealed more intense immunolabeling in Alzheimer's disease (AD) than control brains. The aim of the study is to investigate the level of HGF in cerebrospinal fluid (CSF) from patients with AD. MATERIAL AND METHODS We examined the level of HGF in CSF from 34 AD and 15 age-matched disease control patients by highly sensitive enzyme-linked immunoabsorbent assay (ELISA) system. RESULTS Consistent with the immunohistochemical data, a significantly higher concentration of HGF in AD CSF was found as compared with controls. A significant correlation was also seen between CSF HGF levels and white matter high-signal foci determined on brain magnetic resonance imaging (MRI) in AD patients. CONCLUSION These results indicate that CSF HGF levels correspond with the white matter damage in AD brain.
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Affiliation(s)
- Y Tsuboi
- Department of 5th Internal Medicine, Fukuoka University, Japan
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Armbrust T, Batusic D, Xia L, Ramadori G. Early gene expression of hepatocyte growth factor in mononuclear phagocytes of rat liver after administration of carbon tetrachloride. LIVER 2002; 22:486-94. [PMID: 12445174 DOI: 10.1034/j.1600-0676.2002.01731.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Hepatocyte growth factor (HGF) is a potent hepatocyte mitogen supposed to be a main stimulant of hepatocyte replication during liver regeneration. During acute liver injury, HGF has been detected in nonparenchymal cells of the liver. METHODS We performed in situ hybridization of HGF in rat livers after administration of carbon tetrachloride (CCl4). Mononuclear phagocytes (MNP) were isolated from normal and injured livers and HGF expression was analyzed by Northern blotting, in situ hybridization, and immunoprecipitation of 35S-labeled proteins. RESULTS In situ hybridization of normal liver revealed few HGF positive cells within hepatic sinusoids. In injured livers, the number of cells containing HGF transcripts was increased at 6-24 h after CCl4. Hepatocyte growth factor transcripts in MNP from normal liver were detectable in trace amounts, but became clearly detectable at 6 h and persisted up to 24 h after CCl4 administration. In situ hybridization of MNP isolated from normal liver did not reveal positive cells. Mononuclear phagocytes became HGF-positive when isolated 6 h after CCl4. Hepatocyte growth factor protein was detected in MNP isolated 24 h after CCl4. CONCLUSIONS Hepatocyte growth factor in MNP is not directly induced by interferon-alpha, interferon-gamma or tumour necrosis factor-alpha (TNF-alpha). Stimulated resident mononuclear phagocytes may play a significant role in the increase of HGF expression in liver regeneration after acute liver injury.
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Affiliation(s)
- Thomas Armbrust
- Department of Gastroenterology and Endocrinology, Georg-August-University, Göttingen, Germany
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Galun E, Axelrod JH. The role of cytokines in liver failure and regeneration: potential new molecular therapies. BIOCHIMICA ET BIOPHYSICA ACTA 2002; 1592:345-58. [PMID: 12421677 DOI: 10.1016/s0167-4889(02)00326-9] [Citation(s) in RCA: 83] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The liver is a unique organ, and first in line, the hepatocytes encounter the potential to proliferate during cell mass loss. This phenomenon is tightly controlled and resembles in some way the embryonal co-inhabitant cell lineage of the liver, the embryonic hematopoietic system. Interestingly, both the liver and hematopoietic cell proliferation and growth are controlled by various growth factors and cytokines. IL-6 and its signaling cascade inside the cells through STAT3 are both significantly important for liver regeneration as well as for hematopoietic cell proliferation. The process of liver regeneration is very complex and is dependent on the etiology and extent of liver damage and the genetic background. In this review we will initially describe the clinical relevant condition, portraying a number of available animal models with an emphasis on the relevance of each one to the human condition of fulminant hepatic failure (FHF). The discussion will then be focused on the role of cytokines in liver failure and regeneration, and suggest potential new therapeutic modalities for FHF. The recent findings on the role of IL-6 in liver regeneration and the activity of the designer IL-6/sIL-6R fusion protein, hyper-IL-6, in particular, suggest that this molecule could significantly enhance liver regeneration in humans, and as such could be a useful treatment for FHF in patients.
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Affiliation(s)
- Eithan Galun
- The Goldyne Savad Institute for Gene Therapy, Hadassah Hebrew University Hospital, Ein Kerem, Jerusalem, Israel.
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Gaglio PJ, Liu H, Dash S, Cheng S, Dunne B, Ratterree M, Baskin G, Blanchard J, Bohm R, Theise ND, LaBrecque D. Liver regeneration investigated in a non-human primate model (Macaca mulatta). J Hepatol 2002; 37:625-32. [PMID: 12399229 DOI: 10.1016/s0168-8278(02)00262-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND/AIMS An adequate model to study liver regeneration in humans is presently unavailable. We explored the feasibility of studying liver regeneration in a genetically similar species to man, the non-human primate Rhesus macaque. METHODS Five animals were studied; two underwent 60% hepatectomy, one underwent 30% hepatectomy, and cholecystectomy alone was performed on two animals. Laparoscopic-guided or open liver biopsies were performed on days 1, 2, 7, 14, 21, 30 and 60 following all surgeries. Liver regeneration was evaluated by measuring Ki-67, proliferating cell nuclear antigen expression and mitotic index, calculating changes in the surface area of the liver remnant and assessing intrahepatic production of cytokines. RESULTS Significant liver regeneration was induced in the animals that underwent 60% hepatectomy, peaking between days 21-30 postoperatively. Regeneration was minimal in all other animals studied. Cytokine production followed a similar pattern. Maximal liver regeneration correlated with restoration of surface area in the liver remnant. CONCLUSIONS Sixty percent hepatectomy in a non-human primate model induced significant liver regeneration, maximizing 21-30 days following partial hepatectomy, suggesting a significant interspecies difference when compared to a rodent hepatectomy model. A partial hepatectomy model in Rhesus macaques may allow further characterization of liver regeneration in a species closer to humans.
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Affiliation(s)
- Paul J Gaglio
- Department of Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
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Hata J, Ikeda E, Uno H, Asano S. Expression of hepatocyte growth factor mRNA in rat liver cirrhosis induced by N-nitrosodimethylamine as evidenced by in situ RT-PCR. J Histochem Cytochem 2002; 50:1461-8. [PMID: 12417611 DOI: 10.1177/002215540205001105] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatocyte growth factor (HGF) is a potent inducer of hepatocyte proliferation and is expressed during liver failure. In this study we used the in situ reverse transcriptase-polymerase chain reaction (RT-PCR) method to detect HGF mRNA expression in normal rat livers and cirrhotic rat livers induced by treatment with N-nitrosodimethylamine (DMN). In normal control livers, in situ RT-PCR detected HGF mRNA expression in Ito cells and Kupffer cells, both of which showed rounded morphologies. However, in the cirrhotic livers induced by DMN, HGF mRNA-positive cells were spindle-shaped and surrounded the hepatocytes located around the sinusoids. These cells appeared to be sinusoidal endothelial cells as well as Ito and Kupffer cells. Because it has been suggested that HGF expression is related to transforming growth factor-beta (TGF-beta) levels that may play an essential role in disease progression in cirrhotic livers, TGF-beta mRNA expression in normal and cirrhotic livers was also compared using in situ RT-PCR. Our results confirmed that expression of TGF-beta mRNA co-localized with HGF mRNA expression in the cirrhotic liver.
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Affiliation(s)
- Junko Hata
- Safety Research Department, Pharmaceuticals Development Research Laboratories, Teijin Limited, Tokyo, Japan.
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Kakimoto K, Machigashira M, Ohnishi T, Kajihara T, Semba I, Setoguchi T, Tamura M, Izumi Y, Daikuhara Y. Hepatocyte growth factor in gingival crevicular fluid and the distribution of hepatocyte growth factor-activator in gingival tissue from adult periodontitis. Arch Oral Biol 2002; 47:655-63. [PMID: 12243969 DOI: 10.1016/s0003-9969(02)00050-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Hepatocyte growth factor (HGF), also known as scatter factor, is a broad-spectrum and multifunctional cytokine required for the development, growth and regeneration of various organs and tissues. The expression of HGF in human gingival fibroblasts is induced by inflammatory cytokines such as interleukin 1. Thus, although it is possible that content of HGF in gingival crevicular fluid (GCF) in periodontitis is increased, this has not so far been reported because the volume of GCF is too small to determine HGF by the available enzyme-linked immunosorbent assay (ELISA). A recently developed, highly sensitive ELISA for HGF, with a detection limit of 1 pg/ml sample, has now enabled HGF to be measured in GCF.The mean HGF content in GCF from sites with clinically healthy gingiva, defined by the absence of overt signs of gingival inflammation and a probing depth (PD) <3 mm, was 1.7 ng/ml, and that of periodontitis, defined by obvious alveolar bone loss detected by radiographic examination and a PD> or =3 mm, was 3.23 ng/ml. Although treating the periodontitis did not significantly decrease the HGF concentration despite significantly improved clinical scores such as PD and Gingival Index, the total amount of HGF in GCF did decrease significantly after treatment. HGF was expressed by gingival fibroblasts and inflammatory cells as determined by in situ hybridization. HGF-activator (HGFA), which converts inactive pro-HGF to active mature HGF, was detected in gingival epithelial cells by immunostaining. The expression of HGFA was also confirmed in gingival tissue by reverse transcription-polymerase chain reaction (RT-PCR). These findings indicate that HGF is synthesized and activated in gingiva that is clinically healthy or associated with periodontitis.
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Affiliation(s)
- K Kakimoto
- Department of Biochemistry, Kagoshima University Dental School, 35-1 Sakuragaoka-8, 890-8544, Kagoshima, Japan
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