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Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice.

Abstract

Sepsis and endotoxemia are involved in the development of fulminant hepatic failure, the prognosis of which is extremely poor and the mortality is high, with no available effective therapy. Here, we report that hepatocyte growth factor (HGF) exerts potent antiapoptotic effects in vivo and effectively prevents endotoxin-induced fulminant hepatic failure in mice. The animals were intraperitoneally injected three times with 120 micrograms human recombinant HGF or saline 6 hours and 30 minutes before and 3 hours after an intraperitoneal injection of lipopolysaccharide (LPS) and D-galactosamine (GalN). Administration of LPS + GalN, without HGF, rapidly led to massive hepatocyte apoptosis and severe liver injury, and all mice died of hepatic failure within 8 hours. In contrast, administration of human recombinant HGF strongly suppressed extensive progress of hepatocyte apoptosis and the liver injury induced by LPS + GalN, and 75% of the HGF-treated mice survived. Moreover, HGF strongly induced Bcl-xL expression and blocked apoptotic signal transduction upstream of CPP32 (caspase-3) in the liver, thereby leading to inhibition of massive hepatocyte apoptosis. We suggest that HGF may well have the potential to prevent fulminant hepatic failure, at least through its potent antiapoptotic action.

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  • Authors+Show Affiliations

    ,

    Division of Biochemistry, Department of Oncology, Biomedical Research Center, Osaka University Medical School, Suita, Osaka, Japan.

    , ,

    Source

    Hepatology (Baltimore, Md.) 30:1 1999 Jul pg 151-9

    MeSH

    Animals
    Caspase 3
    Caspases
    Death
    Endotoxins
    Enzyme Activation
    Galactosamine
    Hepatocyte Growth Factor
    Humans
    Lipopolysaccharides
    Liver
    Liver Failure
    Male
    Mice
    Mice, Inbred C57BL
    Recombinant Proteins

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    10385651

    Citation

    Kosai, K, et al. "Hepatocyte Growth Factor Prevents Endotoxin-induced Lethal Hepatic Failure in Mice." Hepatology (Baltimore, Md.), vol. 30, no. 1, 1999, pp. 151-9.
    Kosai K, Matsumoto K, Funakoshi H, et al. Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice. Hepatology. 1999;30(1):151-9.
    Kosai, K., Matsumoto, K., Funakoshi, H., & Nakamura, T. (1999). Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice. Hepatology (Baltimore, Md.), 30(1), pp. 151-9.
    Kosai K, et al. Hepatocyte Growth Factor Prevents Endotoxin-induced Lethal Hepatic Failure in Mice. Hepatology. 1999;30(1):151-9. PubMed PMID: 10385651.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Hepatocyte growth factor prevents endotoxin-induced lethal hepatic failure in mice. AU - Kosai,K, AU - Matsumoto,K, AU - Funakoshi,H, AU - Nakamura,T, PY - 1999/7/1/pubmed PY - 1999/7/1/medline PY - 1999/7/1/entrez SP - 151 EP - 9 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 30 IS - 1 N2 - Sepsis and endotoxemia are involved in the development of fulminant hepatic failure, the prognosis of which is extremely poor and the mortality is high, with no available effective therapy. Here, we report that hepatocyte growth factor (HGF) exerts potent antiapoptotic effects in vivo and effectively prevents endotoxin-induced fulminant hepatic failure in mice. The animals were intraperitoneally injected three times with 120 micrograms human recombinant HGF or saline 6 hours and 30 minutes before and 3 hours after an intraperitoneal injection of lipopolysaccharide (LPS) and D-galactosamine (GalN). Administration of LPS + GalN, without HGF, rapidly led to massive hepatocyte apoptosis and severe liver injury, and all mice died of hepatic failure within 8 hours. In contrast, administration of human recombinant HGF strongly suppressed extensive progress of hepatocyte apoptosis and the liver injury induced by LPS + GalN, and 75% of the HGF-treated mice survived. Moreover, HGF strongly induced Bcl-xL expression and blocked apoptotic signal transduction upstream of CPP32 (caspase-3) in the liver, thereby leading to inhibition of massive hepatocyte apoptosis. We suggest that HGF may well have the potential to prevent fulminant hepatic failure, at least through its potent antiapoptotic action. SN - 0270-9139 UR - https://www.unboundmedicine.com/medline/citation/10385651/Hepatocyte_growth_factor_prevents_endotoxin_induced_lethal_hepatic_failure_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0270913999003213 DB - PRIME DP - Unbound Medicine ER -