Tumor necrosis factor α in the pathogenesis of human and murine fulminant hepatic failure

Streetz, Konrad L.; Leifeld, Ludger; Grundmann, Danja; Ramakers, J.J.M.; Eckert, K.; Spengler, Ulrich; Brenner, David A.; Manns, Michael P.; Trautwein, Christian

doi:10.1053/gast.2000.9364

Cited by 194 publications

(173 citation statements)

References 47 publications

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“…In contrast to Song et al, we used a downstream target of all known death receptors (caspase 8), which is essential in Fas (CD95) as well as in TNF␣ and TNF-related apoptosisinducing ligand-mediated apoptosis of hepatocytes. Because TNF␣ and TNF-related apoptosis-inducing ligand are important mediators of apoptosis in human acute viral hepatitis (6,22), caspase 8 seems to be the more suitable target compared with Fas (CD95) to achieve future therapeutic success in humans with ALF. However, the results in our experiments with Jo-2 were a little less dramatic than in the study from Song et al (13), which may be explained by the more effective delivery of siRNA into the hepatocytes due to repeated application.…”

Section: Discussionmentioning

confidence: 99%

Caspase 8 small interfering RNA prevents acute liver failure in mice

Zender

Hütker²,

Liedtke³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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357

265

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A major concern in therapy of acute liver failure is protection of hepatocytes to prevent apoptosis and maintain liver function. Small interfering RNA (siRNA) is a powerful tool to silence gene expression in mammalian cells. To evaluate the therapeutic efficacy of siRNA in vivo we used different mouse models of acute liver failure. We directed 21-nt siRNAs against caspase 8, which is a key enzyme in death receptor-mediated apoptosis. Systemic application of caspase 8 siRNA results in inhibition of caspase 8 gene expression in the liver, thereby preventing Fas (CD95)-mediated apoptosis. Protection of hepatocytes by caspase 8 siRNA significantly attenuated acute liver damage induced by agonistic Fas (CD95) antibody (Jo2) or by adenovirus expressing Fas ligand (AdFasL). However, in a clinical situation the siRNAs most likely would be applied after the onset of acute liver failure. Therefore we injected caspase 8 siRNA at a time point during AdFasL-and adenovirus wild type (Adwt)-mediated liver failure with already elevated liver transaminases. Improvement of survival due to RNA interference was significant even when caspase 8 siRNA was applied during ongoing acute liver failure. In addition, it is of particular interest that caspase 8 siRNA treatment was successful not only in acute liver failure mediated by specific Fas agonistic agents (Jo2 and AdFasL) but also in acute liver failure mediated by Adwt, which is an animal model reflecting multiple molecular mechanisms involved in human acute viral hepatitis. Consequently, our data raise hope for future successful application of siRNA in patients with acute liver failure.

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Section: Discussionmentioning

confidence: 99%

Caspase 8 small interfering RNA prevents acute liver failure in mice

Zender

Hütker²,

Liedtke³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

357

265

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“…TNF is a critical contributor to inflammation and hepatocyte loss in acute liver injury including after liver resection. 21 TNF is also an important proximal co-mitogen required for priming and proliferation of hepatocytes during liver regeneration. 22 Lack of signaling through the TNF receptor 1 (TNF-R1) in TNF-R1 knockout mice inhibits DNA replication and results in significant mortality following partial hepatectomy.…”

Section: Discussionmentioning

confidence: 99%

A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1-dependent mechanism

Longo¹,

Patel²,

Shrikhande³

et al. 2005

Hepatology

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The liver has a remarkable regenerative capacity, allowing recovery following injury. Regeneration after injury is contingent on maintenance of healthy residual liver mass, otherwise fulminant hepatic failure (FHF) may arise. Understanding the protective mechanisms safeguarding hepatocytes and promoting their proliferation is critical for devising therapeutic strategies for FHF. We demonstrate that A20 is part of the physiological response of hepatocytes to injury. In particular, A20 is significantly upregulated in the liver following partial hepatectomy. A20 protects hepatocytes from apoptosis and ongoing inflammation by inhibiting NF-B. Hepatic expression of A20 in BALB/c mice dramatically improves survival following extended and radical lethal hepatectomy. A20 expression in the liver limits hepatocellular damage hence maintains bilirubin clearance and the liver synthetic function. In addition, A20 confers a proliferative advantage to hepatocytes via decreased expression of the cyclin-dependent kinase inhibitor p21 waf1 . In conclusion, A20 provides a proliferative advantage to hepatocytes. By combining anti-inflammatory, antiapoptotic and pro-proliferative functions, A20-based therapies could be beneficial in prevention and treatment of FHF. (HEPATOLOGY 2005;42:156-164.)

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“…To explore this possibility further at the transcriptional level, we determined the relative expression of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α, Fig. 4A), both of which have been implicated in oval and inflammatory responses in the liver (17)(18)(19)(20). For both IL-6 and TNF-α we observe modest, but significant increases in transcript level consistent with a generalized inflammatory and/or oval cell response (Fig.…”

Section: Transcripts Affected By Reduced Hippo Signaling In Hepatocytmentioning

confidence: 97%

Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver

Liu

Kim

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

643

618

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How organ size is controlled in mammals is not currently understood. In Drosophila the Hippo signaling pathway functions to suppress growth in imaginal discs and has been suggested to control organ size. To investigate the role of hippo signaling in regulation of mammalian organ size we have generated conditional alleles of Sav1 , mst1 , and mst2 , orthologs of Drosophila Salvador and hippo , respectively. Specific deletion of both mst1 and mst2 in hepatocytes results in significantly enlarged livers due to excessive proliferation. By the age of 5–6 months, mst1/2 conditional mutant livers have multiple foci of liver tumors, indicating that the combined activities of mst1 and mst2 act as redundant tumor suppressors in hepatocytes. Similar findings were obtained with liver-specific deletion of Sav1 , a second core Hippo signaling component that facilitates activation of mst1 and mst2 . Tumors from sav1 mutants exhibited varied morphology, suggesting a mixed-lineage origin of tumor-initiating cells. Transcriptional profiling of liver tissues from both mst1/2 and sav1 conditional mutants revealed a network of Hippo signaling regulated genes with specific enrichment for genes involved in immune and inflammatory responses. Histological and immunological characterization of mst1/2 double mutant liver tissues revealed abundant accumulation of adult facultative stem cells termed oval cells in periductal regions. Because oval cells induction is commonly associated with liver injury and tumor formation, it is likely that these cells contribute to the enlarged livers and hepatomas that we observe in sav1 and mst1/2 mutants. Taken together, our results demonstrate that the Hippo signaling pathway is a critical regulator of mammalian liver growth and a potent suppressor of liver tumor formation.

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Tumor necrosis factor α in the pathogenesis of human and murine fulminant hepatic failure

Cited by 194 publications

References 47 publications

Caspase 8 small interfering RNA prevents acute liver failure in mice

Caspase 8 small interfering RNA prevents acute liver failure in mice

A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1-dependent mechanism

Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver

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