transforming-growth-factor-beta and Liver-Failure

Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.

Topics: Angiotensin II; Animals; Humans; Hypertension, Portal; Leptin; Liver Cirrhosis; Liver Failure; Transforming Growth Factor beta

Liver failure after hepatectomy is caused by many factors such as excessive hepatectomy, ischemic-reperfusion injury, postoperative infection, etc. However, apoptosis of hepatocytes is the most important event in the molecular mechanism of liver failure. Liver failure after excessive hepatectomy is characterized by increased apoptosis of hepatocytes and diminished liver regeneration. The former is induced by hypercytokinemia and hyperendotoxemia, and the latter is caused by cell cycle arrest. In ischemic-reperfusion injury of the liver, the apoptosis of hepatocytes is caused by activation of the MMPT and calpain system that are induced by the intracellular accumulation of Ca. The possible mechanism of liver failure in cases with persistent infection is the inhibition of liver regeneration and the induction of apoptosis of hepatocytes due to transforming growth factor-beta 1. The knowledge of these mechanisms will lead to prompt and appropriate treatments for individual patients.

Topics: Animals; Apoptosis; Calcium; Calpain; Cell Membrane Permeability; Cytokines; Endotoxemia; Hepatectomy; Hepatocytes; Humans; Liver Failure; Mitochondria; Postoperative Complications; Reperfusion Injury; Transforming Growth Factor beta; Transforming Growth Factor beta1

To determine any relationship between polymorphisms in the genes encoding tumour necrosis factor alpha (TNFalpha), interleukin-10 (IL-10) and transforming growth factor beta1 (TGFbeta1) and end-stage liver disease.. Whole-blood samples were taken from patients attending the Scottish Liver Transplant Unit with end-stage liver disease (primary biliary cirrhosis, n = 61; alcoholic liver disease, n = 25; primary sclerosing cholangitis, n = 17; viral disease, n = 8; type 1 auto-immune hepatitis, n = 8; acute liver failure, n = 20). DNA was extracted and the polymorphisms at positions TNF -308, IL-10 -1082 and TGFbeta1 +869 and +915 were determined using sequence-specific oligonucleotide probes. Samples were also analysed from normal healthy controls.. There was a significant difference between patients with primary sclerosing cholangitis and healthy controls, with 65% of patients (11/17) possessing at least one TNF2 allele (A at position -308) compared with 38% of controls (P = 0.02). Four of the eight patients with auto-immune hepatitis were homozygous for TNF2 while the other four were heterozygous (P = 0.001). No significant difference between controls and patients was seen in polymorphisms for IL-10 or TGFbeta1. No association between genotype and Child's class was found in primary biliary cirrhosis.. Patients with primary sclerosing cholangitis and auto-immune hepatitis are more likely to possess TNF2 than normal controls. This allele has been associated with an increased production of TNFalpha in vitro and may indicate a predisposition to these inflammatory conditions.

Topics: Adult; Aged; Female; Genetic Markers; Humans; Interleukin-10; Liver Failure; Liver Transplantation; Male; Middle Aged; Polymorphism, Genetic; Probability; Reference Values; Sensitivity and Specificity; Severity of Illness Index; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The limited proliferative ability of hepatocytes is a major limitation to meet their demand for cell-based therapy, bio-artificial liver device, and drug tests. One strategy is to amplify cells at the hepatoblast (HB) stage. However, expansion of HBs with their bipotency preserved is challenging. Most HB expansion methods hardly maintain the bipotency and also lack functional confirmation.. On the basis of analyzing and manipulating related signaling pathways during HB (derived from human induced pluripotent stem cells, iPSCs) differentiation and proliferation, we established a specific chemically defined cocktails to synergistically regulate the related signaling pathways that optimize the balance of HB proliferation ability and stemness maintenance, to expand the HBs and investigate their capacity for injured liver repopulation in immune-deficient mice.. We found that the proliferative ability progressively declines during HB differentiation process. Small molecule activation of Wnt or inhibition of TGF-β pathways promoted HB proliferation but diminished their bipotency, whereas activation of hedgehog (HH) signaling stimulated proliferation and sustained HB phenotypes. A cocktail synergistically regulating the BMP/WNT/TGF-β/HH pathways created a fine balance for expansion and maintenance of the bipotency of HBs. After purification, colony formation, and expansion for 20 passages, HBs retained their RNA profile integrity, normal karyotype, and ability to differentiate into mature hepatocytes and cholangiocytes. Moreover, upon transplantation into liver injured mice, the expanded HBs could engraft and differentiate into mature human hepatocytes and repopulate liver tissue with restoring hepatocyte mass.. Our data contribute to the understanding of some signaling pathways for human HB proliferation in vitro. Simultaneous BMP/HGF induction, activation of Wnt and HH, and inhibition of TGF-β pathways created a reliable method for long-term stable large-scale expansion of HBs to obtain mature hepatocytes that may have substantial clinical applications.

Topics: Animals; Cell Differentiation; Cell Proliferation; Disease Models, Animal; Hedgehog Proteins; Hepatocytes; Humans; Induced Pluripotent Stem Cells; Liver Failure; Mice; Mice, Inbred NOD; Mice, SCID; Signal Transduction; Transforming Growth Factor beta; Wnt Proteins

Major hepatectomy or small-for-size liver transplantation may result in postoperative liver failure. So far, no treatment is available to improve liver regeneration. Herein, we studied whether cilostazol, a selective phosphodiesterase III inhibitor, is capable of improving liver regeneration after major hepatectomy. Sprague-Dawley rats (n = 74) were treated with cilostazol (5 mg/kg daily) or a glucose solution and underwent either 70% liver resection or a sham operation. Before and after surgery, hepatic arterial and portal venous blood flow and hepatic microvascular perfusion were analyzed. Liver morphology, function, and regeneration were studied with histology, immunohistochemistry, western blotting, and bile excretion analysis. Cilostazol significantly increased hepatic blood flow and microcirculation before and after hepatectomy in comparison with sham-operated controls. This was associated with an elevation of hepatic vascular endothelial growth factor expression, an increase of hepatocellular proliferation, and an acceleration of liver regeneration. Furthermore, cilostazol protected the tissue of the remnant liver as indicated by an attenuation of hepatocellular disintegration. In conclusion, cilostazol increases hepatic blood perfusion, microcirculation, and liver regeneration after a major hepatectomy. Thus, cilostazol may represent a novel strategy to reduce the rate of liver failure after both extended hepatectomy and small-for-size liver transplantation.

Topics: Animals; Apoptosis; Bile; Cilostazol; Drug Evaluation, Preclinical; Female; Liver; Liver Circulation; Liver Failure; Liver Regeneration; Models, Animal; Phosphodiesterase 3 Inhibitors; Rats, Sprague-Dawley; Tetrazoles; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

The strategic location of the liver and its metabolic activity make it a key organ regulating homeostasis. Our purpose was to examine its participation in removal of cytokines: interleukin-6 (Il-6), tumor necrosis factor-alpha (TNF-α), hepatocyte growth factor (HGF), and transforming growth factor-beta (TGF-β) from the portal circulation in human. 20 liver donors and 20 patients with end-stage liver failure were included in the study. Their blood was collected during liver transplantation from the portal, hepatic, and peripheral vein, and the hepatic artery and cytokines' concentrations were determined. Using the results the mathematical model of cytokine elimination by the liver was developed. In donors significantly lower levels of IL-6, TNF-α, HGF, and TGF-β were detected in portal blood compared to hepatic vein. In patients with cirrhosis there were no significant differences of IL-6, TNF-α, and TGF-β levels between portal and hepatic veins. Significantly higher level of HGF in hepatic compared to portal vein was observed. In healthy liver elimination of the cytokines prevailed over their synthesis, as reflected by the positive values of the elimination ratios. In the cirrhotic liver elimination ratios of Il-6, HGF, and TGF-β were negative indicating the prevalence of intrahepatic synthesis of cytokines over their removal.

Topics: Adult; Female; Hepatocyte Growth Factor; Humans; Interleukin-6; Liver; Liver Cirrhosis; Liver Failure; Male; Middle Aged; Portal Vein; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Loss of skeletal muscle mass is a poorly understood complication of end-stage liver disease (ESLD). Based on recent stem cell literature, we hypothesized that the potent negative regulator of muscle mass, myostatin, could play a role in the muscle loss associated with ESLD. In this preliminary investigation, we measured myostatin levels in patients undergoing liver transplant evaluation, using a novel enzyme-linked immunosensitivity assay. Myostatin levels were significantly elevated in patients with ESLD compared with healthy controls. These data suggest that myostatin deserves further investigation as a target for therapies designed to preserve muscle mass in patients with ESLD.

Topics: Enzyme-Linked Immunosorbent Assay; Female; Humans; Liver Failure; Liver Transplantation; Male; Malnutrition; Middle Aged; Muscular Diseases; Myostatin; Prothrombin Time; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Wasting Syndrome

To evaluate the effect of thrombopoietin on liver regeneration after hepatectomy and antifibrosis under conditions of liver cirrhosis in rats.. We revealed that platelets induced by thrombopoietin administration promote liver regeneration after hepatectomy in the normal liver.. Seventy percent hepatectomy was carried out in rats, which were subsequently divided into 4 groups: (1) normal group without any treatment, (2) liver cirrhosis (LC) group, (3) combined thrombopoietin and liver cirrhosis (LC+TPO) group, and (4) combined thrombopoietin, antiplatelet serum and liver cirrhosis (LC+TPO+APS) group. Growth kinetics in the liver regeneration and growth factors were analyzed. Liver fibrotic area and activation of hepatic stellate cells were also investigated.. In LC group, liver regeneration was significantly delayed compared with normal group 24 hours after hepatectomy. On the other hand, liver regeneration of LC+TPO group increased significantly compared with LC group, to a level that was the same as that recorded in normal group. In LC group, liver fibrotic area before hepatectomy was significantly higher compared with the normal group. Liver fibrosis of LC+TPO group was significantly reduced compared with LC group. The antifibrotic and liver regeneration promoting effects of LC+TPO group were inhibited by antiplatelet serum in LC+TPO+APS group.. The administration of thrombopoietin reduces liver fibrosis and stimulates regeneration after hepatectomy through increment and accumulation of platelets in the cirrhotic liver. This could be a potentially useful treatment for liver cirrhosis.

Topics: Animals; Disease Progression; Hepatectomy; Hepatocyte Growth Factor; Immunohistochemistry; Insulin-Like Growth Factor I; Liver; Liver Cirrhosis; Liver Failure; Liver Regeneration; Male; Platelet-Derived Growth Factor; Polyethylene Glycols; Postoperative Complications; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Thrombopoietin; Transforming Growth Factor beta

Postoperative infections after hepatectomy sometimes lead to fatal hepatic failure, but the mechanism of the hepatic failure is unclear. Wistar rats underwent 90% hepatectomy, and were then divided into three groups: (i) the SAL group, injected with normal saline; (ii) the LPS group, injected with lipopolysaccharide (LPS) every day for 1 week; and (iii) the LPS plus TGF-Ab (LPS+TGF-Ab) group, injected with LPS with anti-transforming growth factor-beta1 (TGF-beta1) antibody. We investigated survival rates, TGF-beta1 expression in the liver, liver regeneration by proliferating cell nuclear antigen labeling index, hepatocyte apoptosis by single stranded DNA labeling index, and perisinusoidal fibrosis using Masson's trichrome staining. The LPS group (30.4%) had a significantly lower survival rate than the SAL group (84%) and tended to be lower than the LPS+TGF-Ab group (49.4%). Liver regeneration in the LPS group was significantly lower than in the other groups. In the LPS group, hepatocyte apoptosis and perisinusoidal fibrosis was significantly more remarkable, and TGF-beta1 expression was significantly higher than in the SAL group. TGF-beta1 enhanced by LPS plays an important role in the mechanism of hepatic failure by infections after hepatectomy, especially in inhibition of liver regeneration, and induction of hepatocyte apoptosis and perisinusoidal fibrosis.

Topics: Alanine Transaminase; Animals; Apoptosis; Bilirubin; Endotoxins; Fibrosis; Hepatectomy; Hepatocytes; Hyaluronic Acid; Immunohistochemistry; Liver Failure; Liver Regeneration; Male; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar; Survival Rate; Transforming Growth Factor beta; Transforming Growth Factor beta1

Dysbalance in the immune system is perceived as a major factor for adverse outcome after trauma. Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine that regulates proliferation, differentiation of cells, wound healing, and angiogenesis. The influence of TGF-beta1 on trauma patients outcome is still unclear. Injury patterns and clinical outcome parameters of 99 consecutive patients with life-threatening injury and an injury severity score (ISS) > 15 were assessed in a prospective, single-center study at a Level I trauma center. Levels of TGF-beta1 in plasma were measured over a 5-day period by an enzyme-linked immunoabsorbant assay (ELISA). TGF-beta1 plasma levels rise shortly after trauma and gradually drop as the 5th day approaches. Mean and maximal TGF-beta1 plasma levels were significantly higher in patients who developed sepsis and were significantly lower in patients with renal or hepatic failure. Receiver operating characteristics-curve analysis of liver failure shows an area under the curve (AUC) of 0.68 (95%: 0.55-0.81, P = 0.02) and of an AUC of 0.63 (95%: 0.52-0.75, P = 0.03) for renal failure for maximal TGF-beta1 plasma (initial until day 2) levels if lower values represent a more positive test. The data indicate that the increase and decrease of TGF-beta1 plasma levels may contribute to clinical outcome after severe injury. Lower TGF-beta1 levels are associated with liver and renal insufficiency. Higher TGF-beta1 levels 6 h after ICU admission increase the risk of sepsis. TGF-beta1 seems to be an early onset reactant and not a second-line responsive cytokine.

Topics: Accidents, Traffic; Adolescent; Adult; Aged; Area Under Curve; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Injury Severity Score; Liver Failure; Male; Middle Aged; Renal Insufficiency; ROC Curve; Shock, Traumatic; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Trauma Centers; Treatment Outcome; Wound Healing

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).. 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.. 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.. 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.

Topics: Adenoviridae; Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Body Weight; Cytokines; Disease Models, Animal; Galactosides; Gene Expression; Gene Transfer Techniques; Hepatocyte Growth Factor; Hepatocytes; In Situ Nick-End Labeling; In Vitro Techniques; Indoles; Liver Failure; Liver Regeneration; Male; Necrosis; Organ Size; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar; Staining and Labeling; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

A new experimental drug, pirfenidone (5-methyl-1-phenyl-1H-pyridine-one; S-7701), has been reported to have beneficial effects for the treatment of certain fibrotic diseases. We investigated the anti-inflammatory properties in murine endotoxic shock to determine the pharmacological characteristics. The present study describes the prophylactic effect, cytokine regulatory profiles and therapeutic effect of pirfenidone in murine endotoxic shock, which was induced in mice using an intraperitoneal (i.p.) injection of lipopolysaccharide and D-galactosamine. First, we examined the prophylactic effect and cytokine regulatory profiles. A single oral administration of pirfenidone prior to lipopolysaccharide/D-galactosamine challenge inhibited the production of circulating tumor necrosis factor-alpha (TNF-alpha), interleukin-12 and interferon-gamma, markedly enhanced that of interleukin-10, and offered protection from subsequent lethal symptoms in a dose-dependent manner. Second, we examined the therapeutic effect. A single oral administration of pirfenidone 1, 2, 3, 4 and 5 h post lipopolysaccharide/D-galactosamine challenge provided protection against lethal shock in a time-dependent manner. At the histopathological level, apoptotic positive cells were found to be suppressed in the liver. The transforming growth factor (TGF)-beta1 level was markedly elevated in the liver of lipopolysaccharide/D-galactosamine-challenged mice, suppressed in pirfenidone-treated mice. These findings may offer an alternative for both protective and therapeutical treatment of several human acute or chronic inflammatory diseases by pirfenidone.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Galactosamine; Interferon-gamma; Interleukin-10; Interleukin-12; Lipopolysaccharides; Liver; Liver Failure; Mice; Mice, Inbred C57BL; Necrosis; Pyridones; Shock, Septic; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

The present study assessed whether the serum concentrations of tissue inhibitor of metalloproteinase 1 (TIMP-1) and cytokines are altered in patients with fulminant hepatitis and whether plasma exchange affects these concentrations.. Fifteen patients with fulminant hepatitis, 14 patients with severe acute hepatitis, and 20 healthy controls were included in this study. The serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), interleukin 6 (IL-6), transforming growth factor beta (TGF-beta), and TIMP-1 were determined in all patients upon hospital admission and before and after a single course of plasma exchange in the patients with fulminant hepatitis.. Ten out of the 15 patients with fulminant hepatitis and all patients with severe acute hepatitis survived. Serum TNF-alpha, IL-6, TGF-beta, and TIMP-1 levels in patients with fulminant hepatitis were significantly higher than the levels in patients with severe acute hepatitis (p < 0.01). IL-1beta was not detectable in either group. Plasma exchange reduced the increased serum concentrations of TNF-alpha, IL-6, TGF-beta, and TIMP-1 in patients with fulminant hepatitis (p < 0.01).. These data suggest that increased serum levels of TIMP-1 and cytokines may reflect severe hepatic inflammation and that plasma exchange is an effective therapy to reduce these levels.

Topics: Acute Disease; Adult; Cytokines; Hepatitis; Humans; Interleukin-1; Interleukin-6; Liver Failure; Middle Aged; Plasma Exchange; Retrospective Studies; Survival Rate; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha