Humoral inhibitor of rat hepatocyte DNA synthesis from patients with fulminant liver failure

Yamada, Hideaki; Toda, Gotaro; Yoshiba, Makoto; Hashimoto, Naoaki; Ikeda, Yusei; Mitsui, Hiroshi; Kurokawa, Kiyoshi; Sugata, Fumio; Hughes, Robin D.; Williams, Roger L.

doi:10.1002/hep.1840190510

Cited by 13 publications

(9 citation statements)

References 26 publications

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“…On the contrary, the occurrence of reduced AFP levels in patients with severe acute hepatitis while their jaundice was increased may suggest that their liver is in a poor regeneration state, and thus results in a poor outcome. The decreasing AFP Data values are presented as AFP, in ng/ml (total bilirubin, in mg/dl/King's score) a Patient with spontaneous discharge of common bile duct stone Patients underwent b hemodialysis or c plasma exchange d Prolonged prothrombin time more than 50 s e Patient was also positive for IgM anti-HAV and anti-HCV f Patient was also positive for IgM anti-HAV g Patient with lymphoma levels may also be the result of the extensive liver cell necrosis and coexistent increase in levels of circulating hepatotoxic substances 30 in hepatic failure that may inhibit liver regeneration.…”

Section: Discussionmentioning

confidence: 98%

Decreasing serum alpha-fetoprotein levels in predicting poor prognosis of acute hepatic failure in patients with chronic hepatitis B

Yang

Cheng

Lai

et al. 2002

Journal of Gastroenterology

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Section: Discussionmentioning

confidence: 98%

Decreasing serum alpha-fetoprotein levels in predicting poor prognosis of acute hepatic failure in patients with chronic hepatitis B

Yang

Cheng

Lai

et al. 2002

Journal of Gastroenterology

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“…It is thus particularly appropriate for defining the role of cytokines in relation to regener-fulminant liver failure. 34 These molecules have not been identified but are either toxins intrinsic to the fulminant synation, particularly when those cytokines have additional wellcharacterized roles in inflammatory processes. drome or, alternatively, they may subserve a physiological role.…”

Section: 33mentioning

confidence: 99%

Nonparenchymal cells from regenerating rat liver generate interleukin-1? and -1?: A mechanism of negative regulation of hepatocyte proliferation

et al. 1997

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role suppressing hepatocyte proliferation and terminating the Following experimental partial hepatectomy of 70% in the surge of DNA synthesis induced after partial hepatectomy. rat, there is a semisynchronized surge of hepatocyte prolifera-(HEPATOLOGY 1997;26:49-58.) tion that ceases after 48 to 72 hours. Little is known about the determinants governing the termination of the proliferative phase, although transforming growth factor (TGF) b has beenThe majority of hepatocytes in the adult liver are quiescent implicated as an important inhibitor of hepatocyte replication with respect to proliferation. In the rat, only 0.1% of hepatoin this model. We previously reported an additional noncyte nuclei are engaged in replicative DNA synthesis, and TGF-b inhibitor in medium conditioned by nonparenchymal the mitotic rate is 1 in 10,000; 1 figures for human liver are cells isolated from regenerating liver (CM-NPC-Reg) between similar. Adult hepatocytes remain capable of proliferation, 24 and 48 hours after partial hepatectomy, but it was not and, after injury, there is a prompt regenerative response that found in medium conditioned by nonparenchymal cells from recruits mature hepatocytes into the cell cycle. In the rat unoperated control liver. CM-NPC-Reg suppressed replicative after partial hepatectomy of 70%, cells enter the S phase DNA synthesis of primary rat hepatocytes in response to hepawithin 12 to 15 hours, and up to 40% of hepatocytes are in tocyte growth factor (HGF), epidermal growth factor (EGF), the S phase at the peak of DNA synthesis 24 hours after or TGF-a as assessed by 3 H-thymidine incorporation. We now resection.2 At 30 hours' post-resection, there is a synchropresent evidence that interleukin (IL)-1 is the major inhibitor nous wave of hepatocyte mitosis with a histological mitotic of hepatocyte DNA synthesis present in CM-NPC-Reg. IL-1 index of the order of 30%. Hepatocytes may undergo more receptor antagonist abrogated the inhibition, as did antibodies than one round of replication, until the liver regains its forto rat IL-1a and -b; a combination of both antibodies was mer size-typically 7 to 10 days after resection in the rat required, implicating both IL-1a and IL-1b as active constitmodel-when the process terminates. The determinants of uents in CM-NPC-Reg. To investigate in vivo changes in IL-1 hepatocyte proliferation during liver regeneration are highly expression, we assessed expression of IL-1a messenger RNA complex, and different mechanisms operate during the initia-(mRNA) in whole rat liver following partial hepatectomy; tion of DNA synthesis and during the termination of the mRNA was down-regulated at 10 hours in the pre-replicative proliferative surge. Initiating processes within the liver inphase of liver regeneration and up-regulated at 24 hours and clude: 1) disruption of the extracellular matrix, which both 48 hours when proliferation is waning. Rat hepatocytes isorenders hepatocytes more sensitive to growth factors and lated from liver 24 hours after partial hepatectomy showed libe...

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“…There are reports theorizing that circulating toxins may either delay or prevent liver regeneration in patients with fulminant liver failure, disturbing their response to HGF. 53,54 We now plan to see whether administration of a large amount of HGF will improve the prognosis of LEC rats with fulminant hepatitis.…”

Section: Changes In the C-met Mrna Level At Various Phases Of Livermentioning

confidence: 99%

Hepatocyte growth factor and c-met expression in Long-Evans Cinnamon rats with spontaneous hepatitis and hepatoma

et al. 1996

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mal accumulation of copper in the liver of LEC rats, 40 times The Long-Evans Cinnamon (LEC) rat is characterized greater than that in control Long-Evans Agouti rats, whereas by the spontaneous onset of acute and chronic hepatitis, the levels of ceruloplasmin in LEC rat serum were markedly followed by occurrence of liver cancer, and is thus able low. [4][5] It is worth noting that these features of the liver disorto provide a unique experimental model for human geder in LEC rats are very similar to those that characterize netical liver disease, Wilson's disease. HepatocyteWilson's disease. [4][5][6][7] Recently, Wu et al. 8 cloned complemengrowth factor (HGF) is a potent hepatotrophic factor in tary DNAs for a rat gene (Atp7b) homologous to the human liver regeneration, and its expression is up-regulated inWilson's disease gene (ATP7B) and identified a partial deleresponse to liver injuries. We found that the plasma HGF tion in the Atp7b gene in the LEC rat. level in LEC rats rose markedly during the fulminant Hepatocyte growth factor (HGF) was first identified in the hepatitis phase, fell during the phase of chronic/cholanserum of partially hepatectomized rats 9 and purified from rat giofibrosis, and fluctuated during the hepatoma phase.platelets 10 and human plasma. 11,12 HGF is a ligand for the cImmunohistological staining of the liver revealed that met protooncogene product of receptor-type tyrosine kinase, 13-17 the number of HGF-positive cells increased remarkably and is considered to be a major hepatotrophic factor in the during the fulminant hepatitis phase, and that many of induction of mitosis of hepatocytes during liver regenerathese cells were localized at the portal triads. Fewer tion. [18][19][20] Acting as a motogen, HGF induces cell move-HGF-positive cells were observed during the phase of ment, 21,22 and, while acting as a morphogen, it induces the chronic hepatitis. The surface of the hepatocellular carformation of tissue-like structures [23][24][25] for various cell types. cinoma (HCC) cells and the cytoplasm of the nonepithe-The serum levels of HGF are elevated not only in human lial cells in cancerous liver tissues were HGF-positive.patients with fulminant hepatitis, but also in those with The HGF-messenger RNA (mRNA) level in the liver rose chronic hepatitis and cirrhosis. 26 HGF messenger RNA in the fulminant hepatitis phase, fell in the chronic hepa-(mRNA) is expressed in various tissues. 27 It has already been titis phase, and was intermediate or high during the hepreported that HGF production increases in rats injured by atoma phase. The expression of c-met mRNA was strong hepatectomy or CCl 4 , and that nonparenchymal cells produce in the tissues of LEC rats with fulminant hepatitis and, Both the levels of HGF mRNA and the activity of especially, in the cholangiofibrosis tissues. c-met mRNA HGF increase prior to liver regeneration. 28 It has also been was also detected in HCCs. These results suggest that reported that recombinant HGF has promoted remarkable the HGF-c-met system may pla...

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Humoral inhibitor of rat hepatocyte DNA synthesis from patients with fulminant liver failure

Cited by 13 publications

References 26 publications

Decreasing serum alpha-fetoprotein levels in predicting poor prognosis of acute hepatic failure in patients with chronic hepatitis B

Decreasing serum alpha-fetoprotein levels in predicting poor prognosis of acute hepatic failure in patients with chronic hepatitis B

Nonparenchymal cells from regenerating rat liver generate interleukin-1? and -1?: A mechanism of negative regulation of hepatocyte proliferation

Hepatocyte growth factor and c-met expression in Long-Evans Cinnamon rats with spontaneous hepatitis and hepatoma

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