transforming-growth-factor-alpha and Hepatitis

Adiponectin is the most abundant adipokines that plays critical roles in the maintenance of energy homeostasis as well as inflammation regulation. The half-life of adiponectin is very short and the small-molecule adiponectin receptor agonist has been synthesized recently. In the present study, the potential roles of AdipoRon, an adiponectin receptor agonist, in a mouse model of lipopolysaccharide (LPS)/D-galactosamine (D-Gal)-induced acute hepatitis was explored.. BALB/c mice (n = 144, male) were divided into three sets. In set 1, 32 mice were randomized into four groups: the control group, the AdipoRon group, the LPS/D-Gal group, and the AdipoRon + LPS/D-Gal group. The mice in set 1 were sacrificed after LPS/D-Gal treatment, and the plasma samples were collected for detection of tumor necrosis factor-alpha (TNF-α). In set 2, the 32 mice were also divided into four groups similar to that of set 1. The mice were sacrificed 6 h after LPS/D-Gal injection and plasma samples and liver were collected. In set 3, 80 mice (divided into four groups, n = 20) were used for survival observation. The survival rate, plasma aminotransferases, histopathological damage were measured and compared between these four groups.. AdipoRon suppressed the elevation of plasma aminotransferases (from 2106.3 ± 781.9 to 286.8 ± 133.1 U/L for alanine aminotransferase, P < 0.01; from 566.5 ± 243.4 to 180.1 ± 153.3 U/L for aspartate aminotransferase, P < 0.01), attenuated histopathological damage and improved the survival rate (from 10% to 60%) in mice with LPS/D-Gal-induced acute hepatitis. Additionally, AdipoRon down-regulated the production of TNF-α (from 328.6 ± 121.2 to 213.4 ± 52.2 pg/mL, P < 0.01), inhibited the activation of caspase-3 (from 2.04-fold to 1.34-fold of the control), caspase-8 (from 2.03-fold to 1.31-fold of the control), and caspase-9 (from 2.14-fold to 1.43-fold of the control), and decreased the level of cleaved caspase-3 (0.28-fold to that of the LPS/D-Gal group). The number of terminal deoxynucleotidyl transferase-mediated nucleotide nick-end labeling-positive apoptotic hepatocytes in LPS/D-Gal-exposed mice also reduced.. These data indicated that LPS/D-Gal-induced acute hepatitis was effectively attenuated by the adiponectin receptor agonist AdipoRon, implying that AdipoRon might become a new reagent for treatment of acute hepatitis.

Topics: Acute Disease; Animals; Apoptosis; Caspases; Disease Models, Animal; Galactosamine; Hepatitis; Hepatocytes; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Piperidines; Receptors, Adiponectin; Transforming Growth Factor alpha

The aim of this study is to determine whether amitotic division or nuclear proliferation is involved in the formation of giant cells (GCs) in giant cell hepatitis (GCH).. Liver sections from 18 pediatric patients with idiopathic infantile GCH and 12 patients with postinfantile GCH were evaluated for the expression of proliferating cell nuclear antigen (PCNA) and human histone 3 (H3) mRNA, transforming growth factor-alpha (TGF-α), TGF-β1, hepatocyte growth factor (HGF), and epidermal growth factor receptor (EGFR).. Proliferation markers were detected in 1% to 80% in the nuclei of GC and non-GC hepatocytes in 10 of 18 (56%) infantile GCH biopsies and 11 of 12 (92%) postinfantile GCH biopsies, but not in normal liver. The expression of proliferation markers in GCs paralleled that in non-GC hepatocytes (P < 0.05 for both markers). TGF-α and EGFR were detected in both GCs (9/29 and 4/30 patients with infantile or postinfantile GCH, respectively) and non-GC hepatocytes (15/29 and 11/30 patients with infantile or postinfantile GCH, respectively). TGF-β1 and HGF were detected mainly in sinusoidal cells in 20 of 29 and 10 of 30 patients with infantile or postinfantile GCH, respectively; the expression of HGF was positively correlated with PCNA and H3 mRNA in non-GC hepatocytes and with H3 mRNA in GCs (P < 0.01).. Hepatic expressions of nuclear proliferation markers and growth factors were similar in infantile and postinfantile GCH, nuclear proliferation markers were detected in both GCs and non-GC hepatocytes in a high proportion of patients, and expression of HGF correlated positively with the proliferation markers. These data indicate that nuclear proliferation may contribute to the pathogenesis of GCs in at least a proportion of patients with GCH. A model for the pathogenesis of GCH is proposed.

Topics: Adolescent; Adult; Age Factors; Aged; Biomarkers; Biopsy; Cell Proliferation; Child; ErbB Receptors; Female; Giant Cells; Hepatitis; Hepatocyte Growth Factor; Hepatocytes; Histones; Humans; Infant; Male; Middle Aged; Proliferating Cell Nuclear Antigen; RNA, Messenger; Serologic Tests; Statistics, Nonparametric; Transforming Growth Factor alpha; Transforming Growth Factor beta

Transforming growth factor alpha (TGF alpha) is supposed to act as a mitogen for hepatocytes in an autocrine manner in vitro and in vivo. Retarded liver regeneration is a possible reason for poor prognosis of fulminant hepatitis (FH). We analyzed serum TGF alpha levels in patients with FH and patients with acute nonfulminant hepatitis (AH). Also, the relation of those levels to serum hepatocyte growth factor (HGF) levels and their changes after glucagon-insulin (G-I) therapy were studied. Maximal serum TGF alpha levels achieved in each case after admission until recovery from disease or death were correlated positively with maximal serum alanine transaminase (ALT) and total bilirubin levels in patients with AH, but negatively with maximal total bilirubin levels in patients with FH. Maximal serum TGF alpha levels in patients with FH were significantly higher in survivors than in nonsurvivors. Maximal serum HGF levels were positively correlated with maximal serum TGF alpha levels in patients with AH, but not in patients with FH. Multiple regression analysis indicated that G-I therapy was related to the increment of serum TGF alpha levels in patients with FH. These results suggest that serum TGF alpha levels are increased in accordance with liver regeneration after necrosis in patients with AH, but such liver regeneration may be retarded, depending on the extent of liver damage in patients with FH. G-I therapy seems to stimulate liver regeneration after liver damage. The possible contribution of TGF alpha and HGF to liver regeneration merits consideration for recovery from AH.

Topics: Drug Therapy, Combination; Female; Glucagon; Hepatitis; Hepatocyte Growth Factor; Humans; Insulin; Liver Regeneration; Male; Middle Aged; Prognosis; Regression Analysis; Transforming Growth Factor alpha

The present study was undertaken to evaluate the ability of human hepatocytes to respond in culture to various mitotic agents including epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), or serum from patients with fulminant hepatitis. Human hepatocytes were maintained in culture on collagen-coated plates in a chemically and hormonally defined serum-free medium at low cell density. Twelve hours after plating, cultures were treated with increasing amounts of EGF (1-100 ng/mL), TGF-alpha (1-100 ng/mL), or human serum (1%-10%) for 0-96 hours. Proliferative response was assessed by determining against time the rate of DNA synthesis by [3H]thymidine incorporation in DNA, the labeling index, the expression of cyclin A, the amount of DNA, and the number of cells. The rate of DNA synthesis reached a maximum after 48 hours of treatment with 20 ng/mL EGF, 40 ng/mL TGF-alpha, or 5%-10% of human serum (fulminant hepatitis); the average increase with respect to untreated cells was 4.35 times with EGF, 5.4 times with TGF-alpha, and 4-6 times with serum from patients with fulminant hepatitis. The maximum expression of cyclin A coincided with the maximum of DNA synthesis. After 72 hours of treatment with EGF or human serum (fulminant hepatitis), the amount of DNA increased by 75%-100% (P less than 0.001) and the number of cells by 50% (P less than 0.001). These results show that adult human hepatocytes respond to mitogens, as expected from previous studies on animal hepatocytes, and provide experimental basis for future investigations in the field of human liver regeneration.

Topics: Adult; Blood Physiological Phenomena; Cells, Cultured; Cyclins; DNA; Epidermal Growth Factor; Female; Hepatitis; Humans; Liver; Liver Regeneration; Male; Middle Aged; Mitosis; Transforming Growth Factor alpha