Smad3 signaling in the regenerating liver: implications for the regulation of IL-6 expression.

Liver regeneration is vital for graft survival and adequate organ function. Smad activation regulates hepatocyte proliferation and macrophage function. The aim of the current study was to evaluate the impact of Smad3 signaling during liver regeneration in the mouse.

Angiogenesis is crucial for liver regeneration after partial hepatectomy.

Background: Recent studies of hepatic regeneration have mainly focused on the growth of parenchymal cells. However, remodeling of liver vessels seems to be crucial during hepatic regeneration. In this study, we investigated the influence of antiangiogenesis on hepatic regeneration using sFlt-1, a soluble receptor for vascular endothelial growth factor that acts as a dominant negative receptor, and the hepatocyte growth factor antagonist NK4.

Contribution of gut bacteria to liver pathobiology.

Emerging evidence suggests a strong interaction between the gut microbiota and health and disease. The interactions of the gut microbiota and the liver have only recently been investigated in detail. Receiving approximately 70% of its blood supply from the intestinal venous outflow, the liver represents the first line of defense against gut-derived antigens and is equipped with a broad array of immune cells (i.

Inhibition of phosphatidylinositol 3-kinase signaling in hepatic stellate cells blocks the progression of hepatic fibrosis.

Unlabelled: The hepatic stellate cell (HSC) is the primary cell type in the liver responsible for excess collagen deposition during fibrosis. Following a fibrogenic stimulus the cell changes from a quiescent vitamin A-storing cell to an activated cell type associated with increased extracellular matrix synthesis and increased cell proliferation. The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been shown to regulate several aspects of HSC activation in vitro, including collagen synthesis and cell proliferation.

Adeno-associated virus vector-mediated production of hepatocyte growth factor attenuates liver fibrosis in mice.

Purpose: Adeno-associated virus (AAV) vectors can achieve long-term gene expression and are now feasible for use in human gene therapy. We constructed hepatocyte growth factor (HGF) expressing AAV (AAV5-HGF) and examined its effect in two mouse hepatic fibrosis models.

Methods: A model of hepatic fibrosis was established by carbon tetrachloride (CCl(4)) administration in Balb/c mice.

Demonstration of cooperative contribution of MET- and EGFR-mediated STAT3 phosphorylation to liver regeneration by exogenous suppressor of cytokine signalings.

Background/aims: As conditional knockout mice for stat3 are impaired in liver regeneration after partial hepatectomy while those for gp130 have defects in early STAT3 phosphorylation but have normal DNA synthesis, late STAT3 phosphorylation induced independently of gp130 seems to be essential for liver regeneration. Since HGF and EGF can activate STAT3 via gp130-independent MET and EGFR, respectively, we assumed that these factors account for STAT3-dependent liver regeneration. Here, we investigated this hypothesis by introducing suppressor of cytokine signaling (SOCS)-1 and SOCS3, potent negative regulators of STAT3 signaling, selectively in hepatocytes.

Allogeneic bone marrow transplantation for hepatocellular carcinoma: hepatocyte growth factor suppresses graft-vs.-host disease.

Allogeneic bone-marrow transplantation (BMT) can induce a powerful graft-vs.-tumor (GVT) effect not only on hematological malignancies but also on solid tumors. However, graft-vs.

Role of innate immune response in liver regeneration.

Liver regeneration following partial hepatectomy (PH) requires several steps including innate immune responses, particularly interleukin-6 (IL-6) and tumor necrosis factor-(TNF-)alpha production by Kupffer cells, although the activation processes are still unknown. Toll-like receptors (TLR) act as innate immune signal sensors and play central roles in host defense. Myeloid differentiation factor (MyD) 88 is a common adaptor molecule required for signaling mediated by TLR.

Hepatocyte growth factor promotes remodeling of murine liver fibrosis, accelerating recruitment of bone marrow-derived cells into the liver.

Aim: Hepatocyte growth factor (HGF) ameliorates liver fibrosis/cirrhosis in animal models, while the participation of bone marrow-derived cells (BMC) in the repair process of injured organs has recently been reported. In this study we investigated the roles of HGF and BMC in a remodeling process of liver fibrosis.

Methods: C57BL/6 J mice were treated with carbon tetrachloride (CCl(4)) for 10 weeks.

Selective inactivation of NF-kappaB in the liver using NF-kappaB decoy suppresses CCl4-induced liver injury and fibrosis.

Sustained hepatic inflammation induced by various causes can lead to liver fibrosis. Transcription factor NF-kappaB is important in regulating inflammatory responses, especially in macrophages. We presently investigated whether an NF-kappaB decoy, a synthetic oligodeoxynucleotide (ODN) imitating the NF-kappaB binding site, inhibited the inflammatory response after CCl(4) intoxication to prevent CCl(4)-induced hepatic injury and fibrosis.

Oncostatin M gene therapy attenuates liver damage induced by dimethylnitrosamine in rats.

To assess the usefulness of oncostatin M (osm) gene therapy in liver regeneration, we examined whether the introduction of OSM cDNA enhances the regeneration of livers damaged by dimethylnitrosamine (DMN) in rats. Repeated injection of OSM cDNA enclosed in hemagglutinating virus of Japan envelope into the spleen resulted in the exclusive expression of OSM protein in Kupffer cells of the liver, which was accompanied by increases in body weight, liver weight, and serum albumin levels and the reduction of serum liver injury parameters (bilirubin, aspartate aminotransferase, and alanine aminotransferase) and a serum fibrosis parameter (hyaluronic acid). Histological examination showed that osm gene therapy reduced centrilobular necrosis and inflammatory cell infiltration and augmented hepatocyte proliferation.

Blockage of HGF/c-Met system by gene therapy (adenovirus-mediated NK4 gene) suppresses hepatocellular carcinoma in mice.

Background/aims: Hepatocyte growth factor promotes cancer development through cell motility-promoting and angiogenic effects. NK4, a fragment of hepatocyte growth factor, acts as its receptor antagonist. We assessed effects of NK4 gene therapy against human hepatocellular carcinoma cells (HUH7) transplanted into mice.

Contribution of Toll-like receptor/myeloid differentiation factor 88 signaling to murine liver regeneration.

Toll-like receptors (TLRs) act as innate immune signal sensors and play central roles in host defense. Myeloid differentiation factor (MyD) 88 is a common adaptor molecule required for signaling mediated by TLRs. When the receptors are activated, cells bearing TLRs produce various proinflammatory cytokines in a MyD88-dependent manner.

Nuclear factor kappa B decoy oligodeoxynucleotides prevent endotoxin-induced fatal liver failure in a murine model.

Endotoxin syndrome is a systemic inflammatory response mediated by inflammatory cytokines. Nuclear factor kappa B (NF-kappa B) is the dominant regulator of the production of these cytokines by inflammatory cells. The aim of this study was to assess the efficacy of in vivo transfer of synthetic double-stranded oligodeoxynucleotides (ODN) with high affinity against NF-kappa B (NF-kappa B/decoy/ODN) as a therapeutic strategy for treating endotoxin-induced fatal liver injury.