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Michalopoulos GK, Bhushan B. Liver regeneration: biological and pathological mechanisms and implications. Nat Rev Gastroenterol Hepatol 2021; 18:40-55. [PMID: 32764740 DOI: 10.1038/s41575-020-0342-4] [Citation(s) in RCA: 551] [Impact Index Per Article: 137.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/24/2020] [Indexed: 02/08/2023]
Abstract
The liver is the only solid organ that uses regenerative mechanisms to ensure that the liver-to-bodyweight ratio is always at 100% of what is required for body homeostasis. Other solid organs (such as the lungs, kidneys and pancreas) adjust to tissue loss but do not return to 100% of normal. The current state of knowledge of the regenerative pathways that underlie this 'hepatostat' will be presented in this Review. Liver regeneration from acute injury is always beneficial and has been extensively studied. Experimental models that involve partial hepatectomy or chemical injury have revealed extracellular and intracellular signalling pathways that are used to return the liver to equivalent size and weight to those prior to injury. On the other hand, chronic loss of hepatocytes, which can occur in chronic liver disease of any aetiology, often has adverse consequences, including fibrosis, cirrhosis and liver neoplasia. The regenerative activities of hepatocytes and cholangiocytes are typically characterized by phenotypic fidelity. However, when regeneration of one of the two cell types fails, hepatocytes and cholangiocytes function as facultative stem cells and transdifferentiate into each other to restore normal liver structure. Liver recolonization models have demonstrated that hepatocytes have an unlimited regenerative capacity. However, in normal liver, cell turnover is very slow. All zones of the resting liver lobules have been equally implicated in the maintenance of hepatocyte and cholangiocyte populations in normal liver.
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Affiliation(s)
- George K Michalopoulos
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| | - Bharat Bhushan
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Li N, Liu FJ, Li DD, Sun CX, Li J, Qu MH, Cui CP, Zhang DJ. Hepatopoietin Cn (HPPCn) Generates Protective Effects on Acute Liver Injury. Front Pharmacol 2019; 10:646. [PMID: 31333446 PMCID: PMC6620608 DOI: 10.3389/fphar.2019.00646] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 05/20/2019] [Indexed: 01/20/2023] Open
Abstract
Objective: To observe the protective role of hapatopoietin Cn (HPPcn) on acute liver injury. Methods: Six hours after 10 mmol/L CCl4, 150 mmol/L ethanol, or 0.6 mmol/L H2O2 treatment, SMMC7721 human hepatoma cells were incubated with 10, 100, or 200 ng/ml recombinant human HPPCn protein (rhHPPCn) for an additional 24 h. The cell survival rate was analyzed using the CCK-8 assay. The CCl4-induced apoptosis of SMMC7721 cells was detected by flow cytometry. Then, the levels of glutamic oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), malondialdehyde (MDA), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD) in SMMC7721 cell lysates and cell culture supernatant were detected. SMMC7721 cells were treated with different concentrations of rhHPPCn (0, 10, and 100 ng/ml). The cell proliferation indexes (BrdU incorporation and PCNA expression) were detected by immunohistochemistry (IHC). An acute liver injury mouse model was established by a one-time intraperitoneal injection of 20% CCl4 at a volume of 5 ml/kg body weight. One hour after CCl4 injection, 1.25 or 2.5 mg rhHPPCn/12 h/kg body weight was injected via the tail vein. The serum levels of GOT and GPT were detected at different time points. Pathological changes in the liver were evaluated. PCNA expression levels were observed by IHC. Results: rhHPPCn increased the survival rate of SMMC7721 cells and inhibited chemical toxicity-induced cell apoptosis. The levels of GOT, GPT, MDA, and LDH in the cell supernatant were significantly reduced, while GSH-PX and SOD were significantly increased after rhHPPCn treatment in the CCl4-treated SMMC7721 cells. BrdU incorporation and PCNA expression increased in a concentration-dependent manner, indicating that rhHPPCn promotes cell proliferation. The results showed that rhHPPCn significantly reduced the serum levels of GOT and GPT in CCl4-induced acute liver injury mice. rhHPPCn alleviated the tissue damage and increased PCNA expression, indicating the promotion of proliferation after acute injury. Conclusion: rhHPPCn protects hepatocytes from chemical toxins by promoting proliferation and inhibiting apoptosis in vivo and in vitro. Our study provides new insights for the clinical treatment of acute liver injury.
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Affiliation(s)
- Na Li
- School of Pharmacy, Key Laboratory of Applied Pharmacology, Weifang Medical University, Wei Fang, China
| | - Feng-Jiao Liu
- School of Pharmacy, Key Laboratory of Applied Pharmacology, Weifang Medical University, Wei Fang, China
| | - Dan-Dan Li
- Center for Basic Medical Sciences, Sixth Medical Center of PLA General Hospital, Beijing, China
| | - Chun-Xia Sun
- Center for Basic Medical Sciences, Sixth Medical Center of PLA General Hospital, Beijing, China
| | - Jian Li
- School of Pharmacy, Key Laboratory of Applied Pharmacology, Weifang Medical University, Wei Fang, China
| | - Mei-Hua Qu
- School of Pharmacy, Key Laboratory of Applied Pharmacology, Weifang Medical University, Wei Fang, China
| | - Chun-Ping Cui
- State Key Laboratory of Proteomics, National Center of Protein Sciences, Beijing Institute of Life Omics, Beijing, China
| | - Da-Jin Zhang
- Center for Basic Medical Sciences, Sixth Medical Center of PLA General Hospital, Beijing, China
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Lemoine C, Nilsen A, Brandt K, Mohammad S, Melin-Aldana H, Superina R. Liver histopathology in patients with hepatic masses and the Abernethy malformation. J Pediatr Surg 2019; 54:266-271. [PMID: 30528201 DOI: 10.1016/j.jpedsurg.2018.10.083] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 10/30/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND/PURPOSE The Abernethy malformation (AM) is a congenital venous malformation in which the splanchnic venous return bypasses the liver and drains directly into the systemic circulation. This deprives the liver of hepatotrophic growth factors and allows metabolic products of digestion to enter the systemic veins without the benefit of passing through the liver. The histologic features of liver biopsies in children with an AM were reviewed. METHODS A retrospective review of liver biopsies in patients with AM between 1997 and 2017 was performed. Patients were divided into two groups for comparison of histologic features: presence (M+) or absence (M-) of a coexistent liver mass on imaging. Biopsies were reviewed by a pediatric pathologist. Chi-square test was used for statistical analysis between groups. Significance was assigned to p values <0.05. RESULTS Eighteen liver biopsies were reviewed. Masses were present in only 6 patients who had a liver biopsy. Masses were observed with similar frequencies in either type of the Abernethy malformation (I or II). Nine of 12 M- patients and 3/6 M+ patients had the type I AM. Histologically, all patients were noted to have small or absent portal veins. Isolated capillaries were seen more frequently in patients with a known liver mass (p = 0.045), while crowding of portal tracts was more commonly seen in patients without a liver mass (p = 0.019). CONCLUSION Liver biopsies in patients with AM demonstrate abnormal vascular and parenchymal histologic features. Livers with coexistent masses were more commonly found to have features suggesting an increased dependence on arterial blood supply. LEVEL OF EVIDENCE III.
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Affiliation(s)
- Caroline Lemoine
- Division of Transplant Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, USA
| | - Annika Nilsen
- Northwestern University Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, USA
| | - Katherine Brandt
- Division of Transplant Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, USA
| | - Saeed Mohammad
- Division of Gastroenterology, Hepatology & Nutrition, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, USA
| | - Hector Melin-Aldana
- Department of Pathology, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, USA
| | - Riccardo Superina
- Division of Transplant Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, USA.
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Michalopoulos GK. Hepatostat: Liver regeneration and normal liver tissue maintenance. Hepatology 2017; 65:1384-1392. [PMID: 27997988 DOI: 10.1002/hep.28988] [Citation(s) in RCA: 315] [Impact Index Per Article: 39.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 11/30/2016] [Accepted: 11/30/2016] [Indexed: 12/13/2022]
Abstract
In contrast to all other organs, liver-to-body-weight ratio needs to be maintained always at 100% of what is required for body homeostasis. Adjustment of liver size to 100% of what is required for homeostasis has been called "hepatostat." Removal of a portion of any other organ is followed with local regeneration of a limited degree, but it never attempts to reach 100% of the original size. The complex mechanisms involved in this uniquely hepatic process encompass a variety of regenerative pathways that are specific to different types of injury. The most studied form of liver regeneration (LR) is that occurring after loss of hepatocytes in a single acute injury, such as rodent LR after two-thirds partial hepatectomy or administration of damaging chemicals (CCl4 , acetaminophen, etc.). Alternative regenerative pathways become activated when normal regeneration is thwarted and trigger the appearance of "progenitor" cells. Chronic loss of hepatocytes is associated with regenerative efforts characterized by continual hepatocyte proliferation and often has adverse consequences (development of cirrhosis or liver cancer). Even though a very few hepatocytes proliferate at any given time in normal liver, the mechanisms involved in the maintenance of liver weight by this slow process in the absence of liver injury are not as well understood. (Hepatology 2017;65:1384-1392).
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Abstract
Liver regeneration is perhaps the most studied example of compensatory growth aimed to replace loss of tissue in an organ. Hepatocytes, the main functional cells of the liver, manage to proliferate to restore mass and to simultaneously deliver all functions hepatic functions necessary to maintain body homeostasis. They are the first cells to respond to regenerative stimuli triggered by mitogenic growth factor receptors MET (the hepatocyte growth factor receptor] and epidermal growth factor receptor and complemented by auxiliary mitogenic signals induced by other cytokines. Termination of liver regeneration is a complex process affected by integrin mediated signaling and it restores the organ to its original mass as determined by the needs of the body (hepatostat function). When hepatocytes cannot proliferate, progenitor cells derived from the biliary epithelium transdifferentiate to restore the hepatocyte compartment. In a reverse situation, hepatocytes can also transdifferentiate to restore the biliary compartment. Several hormones and xenobiotics alter the hepatostat directly and induce an increase in liver to body weight ratio (augmentative hepatomegaly). The complex challenges of the liver toward body homeostasis are thus always preserved by complex but unfailing responses involving orchestrated signaling and affecting growth and differentiation of all hepatic cell types.
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Affiliation(s)
- George K Michalopoulos
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
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Kang LI, Mars WM, Michalopoulos GK. Signals and cells involved in regulating liver regeneration. Cells 2012; 1:1261-1292. [PMID: 24710554 PMCID: PMC3901148 DOI: 10.3390/cells1041261] [Citation(s) in RCA: 97] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Revised: 11/27/2012] [Accepted: 12/07/2012] [Indexed: 12/11/2022] Open
Abstract
Liver regeneration is a complex phenomenon aimed at maintaining a constant liver mass in the event of injury resulting in loss of hepatic parenchyma. Partial hepatectomy is followed by a series of events involving multiple signaling pathways controlled by mitogenic growth factors (HGF, EGF) and their receptors (MET and EGFR). In addition multiple cytokines and other signaling molecules contribute to the orchestration of a signal which drives hepatocytes into DNA synthesis. The other cell types of the liver receive and transmit to hepatocytes complex signals so that, in the end of the regenerative process, complete hepatic tissue is assembled and regeneration is terminated at the proper time and at the right liver size. If hepatocytes fail to participate in this process, the biliary compartment is mobilized to generate populations of progenitor cells which transdifferentiate into hepatocytes and restore liver size.
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Affiliation(s)
- Liang-I Kang
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Wendy M Mars
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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Decreased expression of the augmenter of liver regeneration results in increased apoptosis and oxidative damage in human-derived glioma cells. Cell Death Dis 2012; 3:e289. [PMID: 22476097 PMCID: PMC3358005 DOI: 10.1038/cddis.2012.25] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The mammalian growth factor erv1-like (GFER) gene encodes a sulfhydryl oxidase enzyme, named Augmenter of Liver Regeneration (ALR). Recently it has been demonstrated that ALR supports cell proliferation acting as an anti-apoptotic factor. This effect is determined by ALR ability to support the anti-apoptotic gene expression and to preserve cellular normoxic conditions. We recently demonstrated that the addition of recombinant ALR (rALR) in the culture medium of H2O2-treated neuroblastoma cells reduces the lethal effects induced by the hydrogen peroxide. Similar data have been reported in the regenerating liver tissue from partially hepatectomized rats treated with rALR. The purpose of the present study was to evaluate the effect of the GFER inhibition, via the degradation of the complementary mRNA by the specific siRNA, on the behaviour of the apoptosis (apoptotic gene and caspase expression and apoptotic cell number) and of the oxidative stress-induced parameters (reactive oxygen species (ROS), clusterin expression and mitochondrial integrity) in T98G glioma cells. The results revealed a reduction of (i) ALR, (ii) clusterin and (iii) bcl-2 and an increase of (iv) caspase-9, activated caspase-3, ROS, apoptotic cell number and mitochondrial degeneration. These data confirm the anti-apoptotic role of ALR and its anti-oxidative properties, and shed some light on the molecular pathways through which ALR modulates its biological effects.
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Polimeno L, Pesetti B, Annoscia E, Giorgio F, Francavilla R, Lisowsky T, Gentile A, Rossi R, Bucci A, Francavilla A. Alrp, a survival factor that controls the apoptotic process of regenerating liver after partial hepatectomy in rats. Free Radic Res 2011; 45:534-549. [PMID: 21291353 DOI: 10.3109/10715762.2011.555482] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Augmenter of Liver Regeneration (Alrp) enhances, through unknown mechanism/s, hepatocyte proliferation only when administered to partially hepatectomized (PH) rats. Liver resection, besides stimulating hepatocyte proliferation, induces reactive oxygen species (ROS), triggering apoptosis. To clarify the role of Alrp in the process of liver regeneration, hepatocyte proliferation, apoptosis, ROS-induced parameters and morphological findings of regenerating liver were studied from PH rats Alrp-treated for 72 h after the surgery. The same parameters, evaluated on regenerating liver from albumin-treated PH rats, were used as control. The results demonstrated that Alrp administration induces the anti-apoptotic gene expression, inhibits hepatocyte apoptosis and reduces ROS-induced cell damage. These and similar data from in vitro studies and the presence of 'Alrp homologous proteins' in viruses as well as in mammals (i) allow to hypothesize that Alrp activity/ies may not be exclusive for regenerating liver and (ii) suggest the use of Alrp in the treatment of oxidative stress-related diseases.
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Affiliation(s)
- Lorenzo Polimeno
- Section of Gastroenterology, Department of Emergency and Organ Transplantation (DETO), University of Bari, Bari, Italy.
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Best DH, Coleman WB. Activation and Regulation of Reserve Liver Progenitor Cells. STEM CELL REGULATORS 2011; 87:93-109. [DOI: 10.1016/b978-0-12-386015-6.00026-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Thirunavukkarasu C, Wang LF, Harvey SA, Watkins SC, Chaillet JR, Prelich J, Starzl TE, Gandhi CR. Augmenter of liver regeneration: an important intracellular survival factor for hepatocytes. J Hepatol 2008; 48:578-88. [PMID: 18272248 PMCID: PMC2954779 DOI: 10.1016/j.jhep.2007.12.010] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2007] [Revised: 11/29/2007] [Accepted: 12/21/2007] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS Augmenter of liver regeneration (ALR), a protein synthesized and stored in hepatocytes, is associated with mitochondria, and possesses sulfhydryl oxidase and cytochrome c reductase activities. We sought to determine the effects of ALR depletion in hepatocytes by antisense oligonucleotide transfection. METHODS Rat hepatocytes in primary culture were transfected with antisense oligonucleotide for ALR mRNA (ALR-AS) or scrambled oligonucleotide. Various analyses were performed at times up to 24h after transfection. RESULTS Treatment with ALR-AS caused a decrease in ALR mRNA, cellular depletion of ALR protein primarily from mitochondria, and decreased viability. Flow cytometric analysis of ALR-AS-transfected hepatocytes stained with annexin-Vcy3 and 7-aminoactinomycin D revealed apoptosis as the predominant cause of death up to 6h; incubation beyond this time resulted in necrosis in addition to apoptosis. ALR-AS-transfection caused release of mitochondrial cytochrome c, activation of caspase-3, profound reduction in the ATP content, and cellular release of LDH. Inhibition of caspase-3 inhibited the early phase of ALR-AS-induced death but not the late phase that included ALR and LDH release. CONCLUSIONS These results suggest that ALR is critically important for the survival of hepatocytes by its association with mitochondria and regulation of ATP synthesis.
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Affiliation(s)
- Chinnasamy Thirunavukkarasu
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, E-1542 BST, 200 Lothrop Street, Pittsburgh, PA 15213, USA
| | - Lian Fu Wang
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, E-1542 BST, 200 Lothrop Street, Pittsburgh, PA 15213, USA
| | | | - Simon C. Watkins
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - J. Richard Chaillet
- Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Thomas E. Starzl
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, E-1542 BST, 200 Lothrop Street, Pittsburgh, PA 15213, USA
| | - Chandrashekhar R. Gandhi
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, E-1542 BST, 200 Lothrop Street, Pittsburgh, PA 15213, USA
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
- VA Medical Center, Pittsburgh, PA, USA
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Fukushima N, Kuromatsu R, Uchiyama D, Itano S, Takata A, Ando E, Sumie S, Torimura T, Uchida M, Nakashima O, Kojiro M, Sata M. Hyperplastic nodular hepatic lesions following end-to-side portacaval shunting in childhood. Intern Med 2007; 46:1203-8. [PMID: 17675770 DOI: 10.2169/internalmedicine.46.6419] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
We describe a 48-year-old man with nodular intrahepatic lesions accompanied by communication between the inferior vena cava and portal systems as well as absence of intrahepatic portal veins. After infection with malaria in childhood, end-to-side portacaval shunting had been performed to treat upper gastrointestinal bleeding at the age of 15 years. A biopsy specimen obtained under ultrasonographic guidance showed hyperplastic nodules suggestive of focal nodular hyperplasia. The estradiol concentration in the blood was elevated (55 pg/ml). This case suggests that portacaval shunting may be associated with hyperplastic liver nodules through hyperestrogenemia and abnormal hepatic hemodynamics.
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Affiliation(s)
- Nobuyoshi Fukushima
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine.
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Vivarelli M, Lauro A, Cucchetti A, D'Errico A, Pironi L, Pinna AD. Effect of total enterectomy, pancreatectomy, and portal vein ligation on liver function and histology: a case report. Transplant Proc 2007; 39:300-302. [PMID: 17275528 DOI: 10.1016/j.transproceed.2006.10.209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2006] [Indexed: 11/24/2022]
Abstract
Impaired hepatic function and histology have been observed in experimental models of diversion of the portal vein blood inflow from the liver and among patients with intestinal failure. Survival after total enterectomy, pancreatectomy, and portal vein ligation, and the effect of such a condition on liver function have never been reported in humans. Herein a 32-year-old woman with familial adenomatous polyposis and multiple desmoid tumors involving the mesentery and the retroperitoneum underwent total enterectomy and pancreatectomy followed by en bloc transplantation of the stomach, small bowel, and pancreas. Due to early graft failure, the patient underwent graftectomy, ligation of the portal vein, and external drainage of the common bile duct. Liver function tests were checked daily and a liver biopsy performed 15 days after graftectomy. The patient died of a ruptured mycotic aneurysm of the abdominal aorta at 27 days after the graftectomy. Liver function tests remained normal throughout the postoperative period; liver biopsy showed normal hepatic architecture with mild portal inflammation and cholestasis and spotty necrosis. Total enterectomy with pancreatectomy and ligation of the portal vein are compatible with survival in humans (at least in the short term), allowing normal hepatic function with minimal histological alterations to the liver.
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Affiliation(s)
- M Vivarelli
- Department of Surgery, University of Bologna, S Orsola Hospital, Bologna, Italy
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Thasler WE, Schlott T, Thelen P, Hellerbrand C, Bataille F, Lichtenauer M, Schlitt HJ, Jauch KW, Weiss TS. Expression of augmenter of liver regeneration (ALR) in human liver cirrhosis and carcinoma. Histopathology 2005; 47:57-66. [PMID: 15982324 DOI: 10.1111/j.1365-2559.2005.02172.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AIMS To determine the expression of a protein termed augmenter of liver regeneration (ALR), recently found to have a specific and beneficial effect on the process of liver regeneration in normal and diseased human liver. METHODS AND RESULTS ALR expression in normal and cirrhotic human livers with various underlying diseases as well as in tissue samples of hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) was analysed by immunohistochemistry and quantitative reverse transciptase-polymerase chain reaction (RT-PCR). Expression analysis of ALR in total liver protein extracts by Western blotting showed mainly dimeric ALR protein. Immunohistochemically, cytosolic and perinuclear immunosignals were found in hepatocytes and cholangiocytes in normal, cirrhotic or cancerous liver tissue and only weak signals in some endothelial cells in normal livers. Quantitative mRNA analysis revealed significantly increased ALR expression in cirrhosis compared with normal liver tissue. In HCC and CCC ALR mRNA expression was also significantly enhanced compared with normal liver tissue, but expression levels did not differ from the matching non-neoplastic tissue in the same patient. CONCLUSIONS The findings suggest an important role for ALR in hepatocellular regeneration in liver cirrhosis as well as in hepatocarcinogenesis and therefore its potential value in the clinical diagnosis of hepatic cirrhosis and cancer.
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Affiliation(s)
- W E Thasler
- Department of Surgery, Ludwig Maximillians University of Munich Hospital Grosshadern, Munich, Germany
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Evert M, Sun J, Pichler S, Slavova N, Schneider-Stock R, Dombrowski F. Insulin receptor, insulin receptor substrate-1, Raf-1, and Mek-1 during hormonal hepatocarcinogenesis by intrahepatic pancreatic islet transplantation in diabetic rats. Cancer Res 2004; 64:8093-100. [PMID: 15520221 DOI: 10.1158/0008-5472.can-04-2040] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Low-number transplantation of pancreatic islets into the livers of diabetic rats leads to transformation of the downstream liver acini into clear-cell foci of altered hepatocytes (FAHs). These FAHs correspond to the glycogen-storing (clear-cell) phenotype of hepatocellular preneoplasias and develop into hepatocellular adenomas (HCAs) and hepatocellular carcinomas (HCCs) within 6 to 24 months. In addition, they show metabolic alterations that resemble well-known insulin effects, most likely constituting the result of the local hyperinsulinemia. Thus, we investigated FAHs, HCAs, and HCCs for altered expression of insulin receptor, insulin receptor substrate-1 (IRS-1), Raf-1 and Mek-1. Light and electron microscopic immunohistochemistry revealed a translocation of insulin receptor from the plasma membrane (normal tissue) into the cytoplasm in clear-cell FAHs and an increase in insulin receptor expression in HCAs and HCCs. FAHs also showed an increase in IRS-1 gene expression, investigated by in situ hybridization and quantitative reverse transcription-PCR. IRS-1, Raf-1, and Mek-1 proteins were strongly overexpressed in FAHs and tumors, as compared with the unaltered liver tissue. These overexpressions were closely linked to the clear-cell phenotype of preneoplastic and neoplastic hepatocytes, because basophilic FAHs (later stages) and basophilic tumors showed no overexpressions. In this endocrine model of hepatocarcinogenesis, severe alterations of insulin signaling were induced by the pathological local action of islet hormones in the livers and may substantially contribute to the carcinogenic process.
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Affiliation(s)
- Matthias Evert
- Institut für Pathologie der Otto-von-Guericke-Universität Magdeburg, Magdeburg, Germany
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Villevalois-Cam L, Rescan C, Gilot D, Ezan F, Loyer P, Desbuquois B, Guguen-Guillouzo C, Baffet G. The hepatocyte is a direct target for transforming-growth factor beta activation via the insulin-like growth factor II/mannose 6-phosphate receptor. J Hepatol 2003; 38:156-63. [PMID: 12547403 DOI: 10.1016/s0168-8278(02)00378-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
BACKGROUND/AIMS The cation-independent mannose 6-phosphate receptor (CIMPR) is overexpressed in hepatocytes during liver regeneration and has been implicated in the maturation of latent pro-transforming growth factor beta (TGFbeta). In this study, we have: (1) kinetically characterized the changes in CIMPR expression in regenerating liver and cultured proliferating hepatocytes; and (2) assessed the contribution of hepatocyte via the CIMPR to latent pro-TGFbeta activation. METHODS The expression of CIMPR protein and mRNA in livers collected after partial hepatectomy and hepatocyte primary cultures was analyzed by Western and Northern blotting. Activity of latent pro-TGFbeta was assessed by inhibition of [3H] methylthymidine incorporation into DNA. RESULTS The expression of the CIMPR protein and/or mRNA progressively increased after 8 h in regenerating liver and 42-46 h in cultured hepatocytes, prior to the onset of DNA replication. Both mature TGFbeta and latent pro-TGFbeta inhibited epidermal growth factor-stimulated DNA synthesis in hepatocytes in a dose-dependent manner. The effect of latent pro-TGFbeta was reversed by two ligands of the CIMPR: beta-galactosidase, a mannose 6-phosphate containing protein, and a CIMPR antibody. CONCLUSIONS (1) The induction of the CIMPR gene during liver regeneration and hepatocyte culture occurs in mid G1 phase; and (2) the CIMPR mediates latent proTGFbeta activation and thus may act, by targeting TGFbeta to hepatocytes, as a negative regulator of hepatocyte growth.
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Affiliation(s)
- Laurence Villevalois-Cam
- INSERM U522, Unité de Recherches Hépatologiques, IFR 97, Hôpital Pontchaillou, 35033 Rennes, France
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Berney T, Kato T, Nishida S, Tector AJ, Mittal NK, Madariaga J, Nery JR, Cantwell GP, Ruiz P, Tzakis AG. Portal versus systemic drainage of small bowel allografts: comparative assessment of survival, function, rejection, and bacterial translocation. J Am Coll Surg 2002; 195:804-13. [PMID: 12495313 DOI: 10.1016/s1072-7515(02)01482-5] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Portal venous drainage of small bowel grafts is theoretically more physiologic than systemic drainage, but is technically more demanding. Comparisons in animal models have not demonstrated a clear advantage of one technique over the other, but clinical data are lacking. STUDY DESIGN Clinical records of 36 patients who underwent 37 small bowel transplantation procedures from January 1995 to August 2001 were reviewed. Portal drainage was performed in 19 patients (PD group). Systemic drainage was performed in 18 patients (SD group). Median followup was 531 days. RESULTS PD and SD patients had similar ICU stays (median 7 versus 9 days) and endotracheal intubation durations (median 3 versus 5 days). All current survivors, with the exception of one patient in each group, are independent from parenteral nutrition. Liver function tests were similar in both groups. There was a twofold increase in tacrolimus dosage in the PD group to achieve similar trough levels indicating a "first-pass" hepatic clearance effect. Cumulative incidence of acute rejection episodes and OKT3-requiring rejection episodes were similar in both groups. To the contrary, a lower incidence of gram-negative rods of Enterococcus sp. in blood or bronchoalveolar lavage suggested that the clearance of translocated intestinal bacteria was more efficient in the PD group. Graft and patient survival rates were similar in both groups. CONCLUSIONS Systemic venous drainage of small bowel transplants is a dependable technique, associated with similar results as portal venous drainage, in terms of overall mortality, morbidity, rejection, function, and patient and graft survival. But attention should be paid to an impaired clearance of intestinal bacterial translocation after systemic drainage.
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Affiliation(s)
- Thierry Berney
- Liver/Gastrointestinal Transplantation, Department of Surgery, University of Miami School of Medicine, Miami, FL 33136, USA
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Gandhi CR, Murase N, Subbotin VM, Uemura T, Nalesnik M, Demetris AJ, Fung JJ, Starzl TE. Portacaval shunt causes apoptosis and liver atrophy in rats despite increases in endogenous levels of major hepatic growth factors. J Hepatol 2002; 37:340-8. [PMID: 12175629 PMCID: PMC2975525 DOI: 10.1016/s0168-8278(02)00165-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND/AIMS The response to the liver damage caused by portacaval shunt (PCS) is characterized by low-grade hyperplasia and atrophy. To clarify mechanisms of this dissociation, we correlated the expression of 'hepatotrophic factors' and the antihepatotrophic and proapoptotic peptide, transforming growth factor (TGF)-beta, with the pathologic changes caused by PCS in rats. METHODS PCS was created by side-to-side anastomosis between the portal vein and inferior vena cava, with ligation of the hilar portal vein. Hepatic growth mediators were measured to 2 months. RESULTS The decrease in the liver/body weight ratio during the first 7 days which stabilized by day 15, corresponded to parenchymal cell apoptosis and increases in hepatic TGF-beta concentration that peaked at 1.4 x baseline at 15 days before returning to control levels by day 30. Variable increases in the concentrations of growth promoters (hepatocyte growth factor, TGF-alpha and augmenter of liver regeneration) also occurred during the period of hepatocellular apoptosis. CONCLUSIONS The development of hepatic atrophy was associated with changes in TGF-beta concentration, and occurred despite increased expression of multiple putative growth promoters. The findings suggest that apoptosis set in motion by TGF-beta constrains the amount of hepatocyte proliferation independently from control of liver volume.
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Affiliation(s)
- Chandrashekhar R Gandhi
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, E-1540 BST, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
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Michalopoulos GK, Bowen WC, Mulè K, Stolz DB. Histological organization in hepatocyte organoid cultures. THE AMERICAN JOURNAL OF PATHOLOGY 2001; 159:1877-1887. [PMID: 11696448 PMCID: PMC1867077 DOI: 10.1016/s0002-9440(10)63034-9] [Citation(s) in RCA: 91] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/15/2001] [Indexed: 01/02/2023]
Abstract
Hepatocytes and other cellular elements isolated by collagenase perfusion of the liver and maintained in defined culture conditions undergo a series of complex changes, including apoptosis and cell proliferation, to reconstruct tissue with specific architecture. Cultures in collagen-coated pleated surface roller bottles, with hepatocyte growth medium medium and in the presence of hepatocyte growth factor (HGF) and epidermal growth factor (EGF), form characteristic and reproducible tissue architecture composed of a superficial layer of biliary epithelial cells, an intermediate layer of connective tissue and hepatocytes, and a basal layer of endothelial cells. Dexamethasone, EGF, and HGF are required for the complete histological organization. Analysis of the structures formed demonstrates that the receptor tyrosine kinase ligands HGF and EGF are required for the presence, growth, and phenotypic maturation of the biliary epithelium on the surface of the cultures and for the formation of connective tissue in the cultures. Dexamethasone, in the presence of HGF and EGF, was required for the phenotypic maturation of hepatocytes. The results demonstrate the role of these molecules for the formation and phenotypic maturation of specific histological elements of the liver and suggest roles for these signaling molecules in the formation and structure of the in vivo hepatic architecture.
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Affiliation(s)
- G K Michalopoulos
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
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Harrison PM, Farzaneh F. Regulation of HGF/SF gene expression in MRC-5 cells by N-acetylcysteine. Biochem Biophys Res Commun 2000; 279:108-15. [PMID: 11112425 DOI: 10.1006/bbrc.2000.3904] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The effect of N-acetylcysteine (NAC) on levels of hepatocyte growth factor/scatter factor (HGF/SF) gene transcripts was investigated in the human lung embryonic fibroblast cell line, MRC-5. NAC increased expression of HGF/SF mRNA, in a dose- and time-dependent fashion, by a mechanism independent of glutathione synthesis but sensitive to oxidant stress induced by H(2)O(2). Using actinomycin D to block RNA synthesis, it was observed that NAC had no effect on the stability of the HGF/SF mRNA transcripts. NAC increased HGF/SF promoter activity in cells transiently transfected with chloramphenicol acetyltransferase (CAT) reporter genes driven by HGF/SF gene 5'-flanking sequences. Primer extension analysis demonstrated that NAC enhanced the expression of HGF/SF mRNA transcribed from the main transcription initiation site. Although the 5' flanking region of the HGF/SF gene contains a sequence at -1019 to -1011 with homology to the NF-kappaB response element, electrophoretic mobility shift assay demonstrated that this site did not bind nuclear factors in MRC-5 cells in the presence or absence of NAC. In contrast to the effect on HGF/SF mRNA, NAC did not increase HGF/SF protein production by MRC-5 cells.
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Affiliation(s)
- P M Harrison
- Institute of Liver Studies, GKT School of Medicine, King's Denmark Hill Campus, Bessemer Road, London, SE5 9PJ, United Kingdom.
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Minami H, Tada K, Chowdhury NR, Chowdhury JR, Onji M. Enhancement of retrovirus-mediated gene transfer to rat liver in vivo by infusion of hepatocyte growth factor and triiodothyronine. J Hepatol 2000; 33:183-8. [PMID: 10952235 DOI: 10.1016/s0168-8278(00)80358-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS Gene transfer using recombinant Moloney murine leukemia viruses (rMoMuLV) requires mitosis of the target cell. Previously, we and others have used partial hepatectomy for induction of hepatocellular proliferation for gene transfer to the liver in vivo by exsanguineous perfusion with rMo-MuLV. We hypothesized that induction of hepatocellular proliferation by combined administration of two hepatocellular mitogens, hepatocyte growth factor (HGF) and triiodothyronine (T3), should permit rMo-MuLV-mediated gene transfer into liver without invasive approaches. METHODS HGF (1 mg/kg) was perfused continuously into the portal vein of Wistar male rats and T3 (2 mg/kg) was injected subcutaneously. Twenty-four hours after injecting HGF and T3, the state of proliferation of hepatocytes was estimated from the incorporation of 5'-bromo-2'-deoxy-uridine (BrdU). The amphotropic retroviral receptor (Ram-1) expression of liver was evaluated at different time points after injecting HGF and T3 by means of Northern blotting using Ram-1 cDNA probe. In order to evaluate the role of hormone treatment on gene transfer, the liver was perfused exsanguineously with rMoMuLV 24 h after injection with hormones. RESULTS Rats treated with a combination of HGF and T3 expressed BrdU and beta-galactosidase in 8.3% and 0.7% of hepatocytes, respectively. On the other hand, there was near absence of gene transfer in untreated rats perfused with rMoMuLV Twenty-four hours after the initial manipulation, abundant expression of Ram-1 mRNA was observed in rat hepatocytes treated with HGF plus T3. CONCLUSIONS Stimulation of hepatocellular mitosis and upregulation of Ram-1 expression by HGF and T3 augment retrovirus-mediated gene transfer into hepatocytes.
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Affiliation(s)
- H Minami
- The Third Department of Internal Medicine, Ehime University School of Medicine, Japan.
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Cheng J, Zhong YW, Liu Y, Dong J, Yang JZ, Chen JM. Cloning and sequence analysis of human genomic DNA of augmenter of liver regeneration. World J Gastroenterol 2000; 6:275-277. [PMID: 11819575 PMCID: PMC4723503 DOI: 10.3748/wjg.v6.i2.275] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Polimeno L, Margiotta M, Marangi L, Lisowsky T, Azzarone A, Ierardi E, Frassanito MA, Francavilla R, Francavilla A. Molecular mechanisms of augmenter of liver regeneration as immunoregulator: its effect on interferon-gamma expression in rat liver. Dig Liver Dis 2000; 32:217-225. [PMID: 10975772 DOI: 10.1016/s1590-8658(00)80824-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND We have shown that the administration of exogenous Augmenter of Liver Regeneration protein in intact rats i) regulates mitochondrial gene expression by inducing the transcription and translation of the nuclear-encoded mitochondrial transcription factor A, and ii) inhibits the lytic activity of liver-resident Natural Killer cells. AIMS The present investigation was carried out to study the effect, in intact rats, of exogenous administration of Augmenter of Liver Regeneration protein on Interferon-gamma, a cytokine produced by activated Natural Killer cells and known to control the expression of mitochondrial transcription factor A, a nuclear gene responsible for mitochondrial metabolism. METHODS Interferon-gamma was measured as messenger RNA in liver-derived mononuclear leukocytes and as protein in liver-derived Natural Killer cells after a single injection of Augmenter of Liver Regeneration protein. RESULTS The data obtained demonstrate that: i) in intact rats, Augmenter of Liver Regeneration protein administration induces a reduction of Interferon-gamma in the liver-resident Natural Killer cells and ii) the administration of Interferon-gamma in 70% hepatectomized rats is followed by a significant reduction both of the mitochondrial transcription factor A expression and of liver regeneration. CONCLUSIONS These data demonstrate the pivotal role of Augmenter of Liver Regeneration as Growth Factor and as immunoregulator by controlling, through Interferon-gamma levels, the mitochondrial transcription factor A expression and the lytic activity of liver-resident Natural Killer cells.
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Affiliation(s)
- L Polimeno
- Dept. Emergency and Organ Transplantation, University of Bari, Italy
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Rocheleau B, Ethier C, Houle R, Huet PM, Bilodeau M. Hepatic artery buffer response following left portal vein ligation: its role in liver tissue homeostasis. THE AMERICAN JOURNAL OF PHYSIOLOGY 1999; 277:G1000-7. [PMID: 10564106 DOI: 10.1152/ajpgi.1999.277.5.g1000] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/14/2023]
Abstract
Occlusion of a lobar portal vein is known to induce atrophy of downstream liver lobes and hypertrophy of contralateral lobes. Changes in portal flow are known to be compensated by changes in hepatic arterial flow, thus defining the hepatic artery buffer response (HABR). To understand the role of liver flow in liver atrophy, we measured portal flow and hepatic artery flow after different degrees of left portal vein stenosis (LPVS). Surgery was performed to obtain 0, 43, 48, 59, 68, 72, 78, and 100% LPVS. Systemic and splanchnic blood flows were measured at 4 h or 7 days after surgery using radiolabeled microspheres. At 4 h, LPVS produced no changes in systemic hemodynamics. Increasing degrees of LPVS produced a significant decrease in left portal flow (P < 0.0001) and a fully compensatory increase in right portal flow (P < 0.0001) without significantly affecting total portal flow. Left hepatic artery flow increased by 210% (P = 0.002), and right hepatic artery flow decreased by 67% (P = 0.05) after full LPVS. There was a significant inverse correlation between portal and arterial flow changes induced by different degrees of LPVS in the left (r(2) = 0. 61) and right (r(2) = 0.41) lobes. Despite this HABR, we observed a reduction in left liver flow (-45%; P = 0.01) and an increase in right liver flow (+230%; P = 0.01) with 100% LPVS. At 7 days, a significant decrease in the weight of left liver lobes (-75%; P < 0. 0001) and a compensatory increase in the weight of the right lobes (+210%; P < 0.0001) were observed with 100% LPVS. Left and right liver flows were similar to results measured at 4 h, and HABR was still present. However, when expressed per gram of liver, liver flows were identical to results obtained with sham animals. Reduction in lobar portal flow is accompanied by an increase in ipsilateral hepatic artery flow and a compensatory increase in portal flow to the rest of the liver. In a given lobe, when compensatory HABR is overcome, liver weight changes occur so that at the end total liver flow per gram of liver tissue is restored. This suggests that in normal conditions liver flow is a major regulator of liver volume.
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Affiliation(s)
- B Rocheleau
- Liver Unit, Centre de recherche du Centre Hospitalier de l'Université de Montréal, Hôpital Saint-Luc, Université de Montréal, Montréal, Québec, Canada H2X 1P1
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Gandhi CR, Kuddus R, Subbotin VM, Prelich J, Murase N, Rao AS, Nalesnik MA, Watkins SC, DeLeo A, Trucco M, Starzl TE. A fresh look at augmenter of liver regeneration in rats. Hepatology 1999; 29:1435-45. [PMID: 10216127 PMCID: PMC2978975 DOI: 10.1002/hep.510290522] [Citation(s) in RCA: 81] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Augmenter of liver regeneration (ALR) is a hepatotrophic protein originally identified by bioassay in regenerating rat and canine livers following partial hepatectomy and in the hyperplastic livers of weanling rats, but not in resting adult livers. The ALR gene and gene product were subsequently described, but little is known about the cellular/subcellular sites of ALR synthesis in the liver, or about the release and dissemination of the peptide. To obtain this information in rats, we raised antibodies in rabbits against rat ALR for development of an enzyme-linked immunosorbent assay (ELISA). ALR concentrations were then determined in intact livers of unaltered weanling and adult rats; in regenerating residual liver after partial hepatectomy; in cultured hepatocytes and nonparenchymal cells (NPCs); and in culture medium and serum. ALR in the various liver cells was localized with immunohistochemistry. In addition, hepatic ALR and ALR mRNA were assayed with Western blotting and reverse-transcriptase polymerase chain reaction (RT-PCR), respectively. The hepatocyte was the predominant liver cell in which ALR was synthesized and stored; the cultured hepatocytes secreted ALR into the medium in a time-dependent fashion. Contrary to previous belief, the ALR peptide and ALR mRNA were present in comparable concentrations in the hepatocytes of both weanling and resting adult livers, as well as in cultured hepatocytes. A further unexpected finding was that hepatic ALR levels decreased for 12 hours after 70% hepatectomy in adult rats and then rose with no corresponding change in mRNA transcripts. In the meantime, circulating (serum) ALR levels increased up to 12 hours and declined thereafter. Thus, ALR appears to be constitutively expressed in hepatocytes in an inactive form, and released from the cells in an active form by unknown means in response to partial hepatectomy and under other circumstances of liver maturation (as in weanling rats) or regeneration.
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Affiliation(s)
- C R Gandhi
- Thomas E. Starzl Transplantation Institute, Veterans Administration Medical Center, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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Panis Y, Lomri N, Emond JC. Early gene expression associated with regeneration is intact after massive hepatectomy in rats. J Surg Res 1998; 79:103-8. [PMID: 9758723 DOI: 10.1006/jsre.1998.5400] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND Liver regeneration occurs promptly after partial hepatectomy, although the factors regulating this response have not been fully clarified. Molecular events in the regenerative response have been widely characterized after 70% hepatectomy which represents a model of "normal" liver regeneration in rats. More extensive resection results in hepatic failure which has been attributed to a critical loss of hepatic mass. It is not known whether the pattern of genes expressed early in regeneration remains intact after lethal hepatectomy. We hypothesize that the increased expression of selected early response genes remains intact after massive hepatectomy. The aim of this study was to compare the expression of selected genes after 70 and 85% hepatectomy. MATERIALS AND METHODS One hundred ten Wistar rats were divided into three groups: control group (sham laparotomy) (n = 30), 70% hepatectomy group (n = 40), and 85% hepatectomy group (n = 40). Animals were sacrificed at intervals. Livers were excised and divided into four equal specimens, snap frozen, and stored at -70 degrees C. RNA was extracted by standard methods and preparations were probed for protooncogenes, c-myc, c-fos, and for hepatocyte growth factor, and its receptor, c-met. After overnight exposure of autoradiographs, quantification was accomplished by densitometry of RNA slot blots. RESULTS After 70% hepatectomy, peaks of maximal expression for both c-myc and c-met were observed after 1 and 12 h. For c-fos, peak of maximal expression was observed at 6 h. For HGF, peak was observed between 12 h and Day 2. After 85% hepatectomy, rats demonstrated similar patterns including peak expression of c-myc at 1 h, but altered peak at 12 h. For c-met, the same pattern was observed between 1 and 12 h. For HGF, two peaks were noted: a first peak at 1 h, and a peak similar to the peak observed after 70% hepatectomy at 12 h. CONCLUSIONS These results suggest that early molecular events which are part of the regenerative response are largely intact after 85% lethal hepatectomy. We propose that liver dysfunction and the failure of regeneration observed after 85% hepatectomy is not due to alteration of early signaling. Further study will be required to define failure of the regeneration program in this model.
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Affiliation(s)
- Y Panis
- Liver Transplant Program, University of California, San Francisco, California 94143, USA
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Liu Q, Kabeer M, Callahan M, Orazi A, Pescovitz MD, Grosfeld JL. Mesocaval shunt inhibits primary and metastatic hepatoma growth and enhances apoptosis. J Pediatr Surg 1998; 33:1128-33. [PMID: 9694108 DOI: 10.1016/s0022-3468(98)90545-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND Previous reports indicate that hepatocyte growth factor and other hepatic trophic factors reach the liver presumably by portal venous inflow and stimulate experimental hepatic tumor growth, invasion, and metastasis. This study tests this hypothesis by evaluating whether a mesocaval shunt (MCS) alters hepatic tumor growth, the mitotic rate, apoptosis, and incidence and growth of lung metastasis in rats with implanted hepatoma. METHODS Morris hepatoma (1 x 10(5)) cells were implanted intrahepatically in 19 ACI rats. One week after implantation, 10 rats underwent MCS operation and nine controls a sham operation. Rats were killed 21 days after the operation to assess tumor volume, tumor cell mitosis, apoptosis, area of tumor necrosis, pulmonary metastases and percentage of lung tumor area. RESULTS Mesocaval shunt induced a significant increase in the rate of tumor apoptosis (25 +/- 5 v 14 +/- 6, P < .01) and the percentage of area of tumor necrosis (29% +/- 17% v 13% +/- 8%, P < .05), a decreased tumor volume (839 +/- 1,195 v 2,909 +/- 2,572, P < .05), a reduction in tumor mitosis (70 +/- 28 v 93 +/- 11, P < .05) and decreased percentage area of pulmonary metastatic tumor (9.8 +/- 6.8 v 18.8 +/- 14, P < .05). CONCLUSION These observations show that growth of intrahepatic tumor is influenced by portal venous inflow and suggest that MCS or other methods of regulating portal vein flow may be useful as adjunctive therapy in the treatment of advanced hepatoma.
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Affiliation(s)
- Q Liu
- Department of Surgery, Indiana University School of Medicine, Indianapolis, USA
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Miwa Y, Harrison PM, Farzaneh F, Langley PG, Williams R, Hughes RD. Plasma levels and hepatic mRNA expression of transforming growth factor-beta1 in patients with fulminant hepatic failure. J Hepatol 1997; 27:780-8. [PMID: 9382963 DOI: 10.1016/s0168-8278(97)80313-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND/AIMS Transforming growth factor-beta1 is an important cytokine involved in cell growth and inflammation which has been shown to be inhibitory to hepatic DNA synthesis. The aim of this study was to investigate the plasma levels and hepatic mRNA expression of transforming growth factor-beta1 in patients with fulminant hepatic failure in whom liver regeneration may be impaired. METHODS Plasma levels of transforming growth factor-beta1 and human hepatocyte growth factor were measured in 57 fulminant hepatic failure patients and 20 healthy volunteers by ELISA. Northern blot analysis of transforming growth factor-beta1 and H3 histone, a marker for liver proliferation, was performed in liver tissue of 14 fulminant hepatic failure patients. RESULTS The plasma levels of total transforming growth factor-beta1 in fulminant hepatic failure patients on admission (median 38.8 ng/ml, range 8.4-108 ng/ml) were significantly higher than those in control subjects (23.0 ng/ml, 8.5-34.9 ng/ml, p<0.001). Significantly higher levels were observed in non-A, non-B hepatitis patients (57.9 ng/ml, 38.8-108 ng/ml, n=10, p<0.001) compared to patients with paracetamol overdose (37.1 ng/ml, 8.4-72.5 ng/ml, n=47). In contrast, the plasma levels of free transforming growth factor beta1 were greater in paracetamol overdose (623 pg/ml, 46.7-1241 pg/ml, n=21) than in non-A, non-B hepatitis (131 pg/ml, 77.2-254 pg/ml, n=9), with both being higher than control (72.3 pg/ml, 28.7-108, n=7, p<0.001). The plasma levels of human hepatocyte growth factor in patients with paracetamol overdose (7.04 ng/ml, 1.00-62.4 ng/ml) were significantly higher than those in patients with non-A, non-B hepatitis (4.48 ng/ml, 0.74-9.10 ng/ml, p<0.05). Northern blots showed increased mRNA expression of transforming growth factor-beta1 in paracetamol-overdose patients (n=8, p<0.05), but not in patients with non-A non-B hepatitis (n=6), compared to controls (n=4). CONCLUSIONS The increased circulating plasma TGF-beta1 in FHF may be part of the tissue repair process in fulminant hepatic failure. In patients with non-A, non-B hepatitis, the increased total transforming growth factor-beta1 together with a less elevated hepatocyte growth factor could be related to impaired liver regeneration in this group.
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Affiliation(s)
- Y Miwa
- Institute of Liver Studies, King's College School of Medicine and Dentistry, London, UK
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Ueno S, Kobayashi Y, Kurita K, Tanabe G, Aikou T. Effect of prior portosystemic shunt on early hepatic hemodynamics and sinusoids following 84% hepatectomy in dogs. RESEARCH IN EXPERIMENTAL MEDICINE. ZEITSCHRIFT FUR DIE GESAMTE EXPERIMENTELLE MEDIZIN EINSCHLIESSLICH EXPERIMENTELLER CHIRURGIE 1995; 195:1-8. [PMID: 7784699 DOI: 10.1007/bf02576768] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The effects of a prior portosystemic shunt (PSS) on the hepatic hemodynamics and sinusoids shortly after an 84% hepatectomy (Hx) were investigated in dogs. Fifteen mongrel dogs were divided into three groups, a 70% Hx group (n = 5), an 84% Hx group (n = 5) and an 84% Hx+PSS group (n = 5). In the last group, a shunt was inserted between the splenic and femoral veins prior to the hepatectomy. The systemic and hepatic hemodynamics were measured, before and 180 min after the hepatectomy, and the remaining liver tissue was then examined immunohistochemically by light microscopy using the thrombomodulin (TM) staining method. The postoperative portal vein pressure and the vascular resistance were significantly lower in the PSS group than in the 84% non-PSS group. The total postoperative hepatic blood flow was higher in the 84% non-PSS group than in the other two groups. Immunohistochemical observation after TM staining indicated that the sinusoidal endothelial cells in the 84% non-PSS group were markedly damaged 3 h after surgery. We conclude that a prior PSS improves the hepatic hemodynamics and is beneficial to the sinusoids within the first few hours of an 84% hepatectomy in dogs.
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Affiliation(s)
- S Ueno
- First Department of Surgery, Kagoshima University School of Medicine, Japan
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Keratinocyte growth factor–just another mitogen or the “holy grail” that regulates liver regeneration? Hepatology 1995. [DOI: 10.1002/hep.1840220640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Gohda E, Nakamura S, Yamamoto I, Minowada J. Hepatocyte growth factor--pleiotropic cytokine produced by human leukemia cells. Leuk Lymphoma 1995; 19:197-205. [PMID: 8535210 DOI: 10.3109/10428199509107889] [Citation(s) in RCA: 28] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatocyte growth factor (HGF) was identified, purified and molecularly cloned as a potent mitogen for mature rat hepatocytes in primary culture. It is one of the largest cytokines and is composed of disulfide-linked subunits of approximately 60 (heavy chain) and 35 kilodaltons (light chain). Recent observations revealed that HGF is mitogenic to various epithelial cells other than hepatocytes and to endothelial cells, and that it also acts as a motogen, morphogen and tumor-suppressor as well as a mitogen. These various biological activities of HGF are presumably transduced through the same receptor, c-Met, which is a member of the tyrosine kinase receptor family. Although it shows multiple biological activities on cells in culture, HGF is most likely the physiological hepatotrophic factor which triggers liver regeneration. It may also function as a renotrophic and pulmotrophic factor after tissue injury. HGF production in the liver, kidney and lung increases after injury to these organs. An elevated HGF level may act as an inducer of compensatory DNA synthesis. The regulation of HGF production is, therefore, important for the control of organ regeneration. HGF is produced mainly by mesenchymal cells such as fibroblasts and vascular smooth muscle cells. Various types of human leukemia cells also secrete HGF both in vitro and in vivo. Some biological activities of HGF on hematopoietic cells, including co-mitogenic activity on myeloid leukemia cell lines, were recently demonstrated. HGF gene expression and the protein production in leukemia and fibroblast cells are modulated by various cytokines and hormones. Those modulators may indirectly affect organ regeneration and other biological processes by controlling HGF production.
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Affiliation(s)
- E Gohda
- Department of Immunochemistry, Faculty of Pharmaceutical Sciences, Okayama University, Japan
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Affiliation(s)
- X Wang
- Dept. of Surgery, Lund University Hospital, Sweden
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Francavilla A, Hagiya M, Porter KA, Polimeno L, Ihara I, Starzl TE. Augmenter of liver regeneration: its place in the universe of hepatic growth factors. Hepatology 1994. [PMID: 8076931 DOI: 10.1002/hep.1840200328] [Citation(s) in RCA: 88] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- A Francavilla
- Pittsburgh Transplant Institute, University of Pittsburgh Medical Center, Pennsylvania 15213
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Heparin-hepatocyte growth factor complex with low plasma clearance and retained hepatocyte proliferating activity. Hepatology 1994. [PMID: 8045504 DOI: 10.1002/hep.1840200223] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Webber EM, Godowski PJ, Fausto N. In vivo response of hepatocytes to growth factors requires an initial priming stimulus. Hepatology 1994. [PMID: 8294105 DOI: 10.1002/hep.1840190230] [Citation(s) in RCA: 136] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Although growth factor effects have been studied in cultured hepatocytes, little information exists as to whether these factors can trigger hepatocyte replication in vivo. In this study we infused epidermal growth factor, transforming growth factor-alpha and hepatocyte growth factor directly into the portal vein of rats for 24 hr to see whether they could induce DNA synthesis in normal livers or in livers subjected to one-third hepatectomy. Infusion of transforming growth factor-alpha or epidermal growth factor at doses up to 80 micrograms/24 hr had little effect on hepatic DNA synthesis in normal liver, whereas the monomeric and heterodimeric forms of hepatocyte growth factor generally produced increases of less than threefold in hepatic DNA synthesis. In contrast, after one-third hepatectomy infusion of epidermal growth factor, transforming growth factor-alpha or hepatocyte growth factor produced dose-dependent increases in hepatic DNA synthesis. At a dose of 40 micrograms/24 hr, epidermal growth factor increased DNA synthesis threefold, whereas transforming growth factor-alpha or hepatocyte growth factor increased DNA synthesis to greater than six times that in rats that had undergone hepatectomy alone. Furthermore, infusion of these growth factors, with or without one third-hepatectomy, induced the expression of transforming growth factor-alpha mRNA in the liver. The pattern of protooncogene expression induced by one-third hepatectomy was studied to determine the effect of this procedure in sensitizing the liver to the growth factors. Compared with the well-characterized two-thirds hepatectomy system, there was a similar but smaller increase in c-myc expression but no induction of c-jun expression.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- E M Webber
- Department of Pathology and Laboratory Medicine, Brown University School of Medicine, Providence, Rhode Island 02912
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Francavilla A, Zeng Q, Polimeno L, Carr BI, Sun D, Porter KA, Van Thiel DH, Starzl TE. Small-for-size liver transplanted into larger recipient: a model of hepatic regeneration. Hepatology 1994; 19:210-216. [PMID: 8276357 DOI: 10.1002/hep.1840190131] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Orthotopic liver transplantation was performed in 60 recipient rats weighing 200 to 250 gm. Sixty rats of the same strain were used as liver donors, 30 weighing 100 to 140 gm (small for size) and the other 30 weighing 200 to 250 gm (same size). After 1, 2, 3, 4, 7 and 14 days (n = 5 each) DNA synthesis, nuclear thymidine labeling and mitoses were increased in both the small-for-size and same-size groups, but significantly more in the former. These changes were maximal after 48 to 72 hr, similar to but later than the well-known regeneration response after partial hepatectomy, which peaks at 24 hr in rats. Indirect indexes of regeneration of the transplanted livers also were measured: plasma or serum ornithine decarboxylase; insulin and glucagon serum levels; estradiol and testosterone serum levels (and their nuclear and cytosolic receptors); and transforming growth factor-beta, c-Ha-ras and c-jun mRNA expressions. With the small-for-size transplantation, these followed the same delayed pattern as the direct regeneration parameters. The small livers gradually increased in size over the course of 1 to 2 wk and achieved a volume equal to that of the liver originally present in the recipient. In contrast, no significant liver weight gain occurred in the transplanted livers from same-size donors despite the evidence of regeneration by direct indexes, but not by most of the surrogate parameters, including ornithine decarboxylase.
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Affiliation(s)
- A Francavilla
- Department of Surgery, University of Pittsburgh, Pennsylvania 15240
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40
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Ni N, Yager JD. Comitogenic effects of estrogens on DNA synthesis induced by various growth factors in cultured female rat hepatocytes. Hepatology 1994. [PMID: 7506224 DOI: 10.1002/hep.1840190128] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
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41
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Tani M, Tomiya T, Yamada S, Hayashi S, Yahata K, Tamura Y, Akiyama M, Kawai S, Masaki N, Fujiwara K. Regulating factors of liver regeneration after hepatectomy. Cancer Chemother Pharmacol 1994; 33 Suppl:S29-32. [PMID: 8137481 DOI: 10.1007/bf00686664] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The factors regulating liver regeneration were studied by measuring changes in the liver volume and serum hepatocyte growth factor (HGF) levels after hepatectomy. Changes in the liver volumes were studied in 68 hepatectomized patients, including (A) hepatoma patients who had chronic hepatitis or liver cirrhosis (n = 44) and (B) metastatic liver cancer patients who had normal liver parenchyma (n = 24). The hepatic volume increased by 13.8% of the remnant hepatic volume in group A and by 49.1% in group B. The examined factors included the percentage of resected liver volume (%RLV) and the results of laboratory tests. Regression analysis showed that in group A, both %RLV (beta = 0.46) and the serum total bilirubin (T-Bil) level (beta = -0.33) correlated significantly with the extent of liver regeneration and that in group B, only %RLV (beta = 0.78) correlated significantly with the regeneration. Serum HGF levels after hepatectomy were studied in 21 hepatectomized patients, including 11 hepatoma patients and 10 patients with some types of metastatic liver cancer. Serum HGF levels increased significantly after surgery in all 21 patients. Regression analysis, however, showed that the change in HGF was related to liver cirrhosis (beta = 0.46) and to the maximal postoperative T-Bil level (beta = 0.51) but not to the extent of liver regeneration after hepatectomy. These results suggest that liver regeneration is regulated primarily by factors relating to the percentage of the resected liver parenchyma and that serum HGF levels do not directly relate to liver regeneration after surgery.
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Affiliation(s)
- M Tani
- Division of General Surgery, International Medical Center of Japan, Tokyo
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Stimulation of liver growth by exogenous human hepatocyte growth factor in normal and partially hepatectomized rats. Hepatology 1993. [PMID: 8244271 DOI: 10.1002/hep.1840180625] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Abstract
Over 80 peptides and amines secreted by more than 20 different types of neuroendocrine cells scattered throughout the gut have been identified. The physiologic function and clinical relevance of many of these hormones await elucidation. Nevertheless, the clinical use of these agents in either diagnostic or therapeutic modalities has greatly expanded the appreciation of the relevance of many of these peptides to malignant and nonmalignant pathobiology.
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Affiliation(s)
- I M Modlin
- Department of Surgery, Yale University School of Medicine, New Haven, Connecticut
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Hashimoto M, Kothary PC, Raper SE. The effects of transforming growth factor alpha and somatostatin on regenerating hepatocytes in the rat. REGULATORY PEPTIDES 1993; 44:49-59. [PMID: 8097889 DOI: 10.1016/0167-0115(93)90129-v] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Transforming growth factor alpha (TGF alpha) stimulates DNA synthesis in adult rat hepatocytes, and plays a physiological role after partial hepatectomy by an autocrine mechanism. Somatostatin (SS-14) is a potent inhibitor of gastrointestinal function and inhibits proliferation in various cell types. We examined the proliferative effect of TGF alpha and the inhibitory effect of SS-14 on hepatocytes isolated at various times after partial hepatectomy. To study the mechanism of SS-14 further, we treated rats with the long acting SS-14 analog, octreotide, before or after 70% hepatectomy to determine whether or not a differential effect could be seen. We confirmed the proliferative effects of TGF alpha, and the inhibitory action of SS-14 in the early phase of liver regeneration in vitro. Regenerating hepatocytes isolated from hepatectomized livers respond to TGF alpha only at early time points (2 h) but do not respond to SS-14. In addition, the long acting SS-14 analog, octreotide, inhibited hepatic regeneration only when administered prior to hepatectomy. We conclude that exogenous peptide stimulation is effective only in the early phase of the hepatic proliferative response. After the initial changes brought about by hepatectomy, subsequent steps of the regenerative process appear refractory to external stimuli.
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Affiliation(s)
- M Hashimoto
- Department of Surgery, University of Michigan Medical School, Ann Arbor
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Abstract
Over a period of 33 years, it has become possible to successfully transplant individual intra-abdominal viscera or combinations of these organs. The consequences have been, first, new information about the metabolic interrelations that the visceral organs have in disease or health; second, the addition of several procedures to the treatment armamentarium of gastrointestinal diseases; and third, a more profound understanding of the means by which all whole organ grafts are accepted.
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Affiliation(s)
- T E Starzl
- Pittsburgh Transplant Institute, University of Pittsburgh Health Science Center, Pennsylvania
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Francavilla A, Azzarone A, Carrieri G, Cillo U, Van Thiel D, Subbottin V, Starzl TE. Administration of hepatic stimulatory substance alone or with other liver growth factors does not ameliorate acetaminophen-induced liver failure. Hepatology 1993. [PMID: 8444417 DOI: 10.1002/hep.1840170313] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Sixty-two beagle dogs were given three doses of acetaminophen over a period of 24 hr in a fulminant liver failure model that is 70% lethal in 72 hr. Treatment of the animals with hepatic stimulatory substance alone or in a mixture with insulin, transforming growth factor-alpha and insulin-like growth factor II had no effect on mortality. Evidence of maximum regeneration with a mitotic index 20 to 25 times resting was the same in treated and untreated animals. Similarly, the biochemical and hematological indexes of liver injury were unaffected by therapy. These studies illustrate the futility of treating fulminant liver failure with exogenous growth factors that apparently are already present in large amounts in the natural response to liver injury. The results suggest that on-going liver injury by mechanisms other than lack of growth factors is the central problem of fulminant liver failure. If so, provision of regeneration-stimulating substance is an inappropriate therapeutic strategy.
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Affiliation(s)
- A Francavilla
- Pittsburgh Transplant Institute, University of Pittsburgh Health Science Center, Pennsylvania 15213
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Barone M, Panella C, Angelini A, Romanelli D, Francavilla A. Studies in vitro on the influence of ursodeoxycholate sodium salt (UDC) on hepatocyte proliferation. J Surg Oncol 1993; 3:8-13. [PMID: 8503985 DOI: 10.1002/jso.2930530504] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
In this study the influence of sodium ursodeoxycholate (UDC) on hepatocyte replicative activity was evaluated using quiescent or primed hepatocytes obtained from normal rats or from rats fed with a protein-free diet, respectively. At physiological concentrations UDC stimulated proliferation in quiescent or primed hepatocytes cultured in minimum essential medium plus insulin, and augmented the replicative activity in hepatocytes already stimulated by low concentration of epidermal growth factor and normal rat serum. However, UDC was not the only bile salt (BS) to show this stimulatory effect on hepatocyte proliferation. The stimulatory activity of BSs was not correlated with their degree of hydrophilia.
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Affiliation(s)
- M Barone
- Department of Gastroenterology, University of Bari, Italy
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Affiliation(s)
- A Francavilla
- Department of Gastroenterology, University of Bari, Italy
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Francavilla A, Azzarone A, Carrieri G, Scotti-Foglieni C, Zeng QH, Cillo U, Porter K, Starzl TE. Effect on the canine Eck fistula liver of intraportal TGF-beta alone or with hepatic growth factors. Hepatology 1992. [PMID: 1427665 DOI: 10.1002/hep.1840160524] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Transforming growth factor-beta canceled the hepatocyte proliferation caused by transforming growth factor-alpha when the two substances were mixed and administered through a disconnected central portal vein branch after creation of an Eck fistula. In contrast, transforming growth factor-beta had no antidotal action on the stimulatory effects of insulin or full test doses of insulinlike factor-2, hepatocyte growth factor, epidermal growth factor or triiodothymanine. A minor antidotal effect on hepatic stimulatory substance activity could be detected, but only with hepatic stimulatory substance was given in doses smaller than those known to cause maximum stimulatory response. These results suggest a highly specific pharmacological and physiological interaction between transforming growth factor-alpha and transforming growth factor-beta in the modulation of liver growth control.
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Affiliation(s)
- A Francavilla
- Transplantation Institute, University Health Center of Pittsburgh, Pennsylvania 15213
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