Cholestasis induces murine hepatocyte apoptosis and DNA synthesis with preservation of the immediate-early gene response

Bird, Mark A.; Lange, Patty A.; Schrum, Laura W.; Grisham, Joe W.; Rippe, Richard A.; Behrns, Kevin E.

doi:10.1067/msy.2002.122375

Cited by 15 publications

(7 citation statements)

References 36 publications

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“…During the process of BDL-induced hepatitis, hepatocyte proliferation is noted in response to necrosis and apoptosis (3,18). In a rat BDL model, there was a correlation between hepatic HGF mRNA levels and PCNA scores: In the HGF mRNA-decreased liver, hepatic growth became mild (31).…”

Section: Discussionmentioning

confidence: 96%

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Antinecrotic and antiapoptotic effects of hepatocyte growth factor on cholestatic hepatitis in a mouse model of bile-obstructive diseases

Mizuno²,

Nakamura³

2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Cholestasis, an impairment of bile outflux, frequently occurs in liver diseases. In this process, an overaccumulation of bile acids causes hepatocyte necrosis and apoptosis, leading to advanced hepatitis. Hepatocyte growth factor (HGF) is mitogenic toward hepatocytes, but it is still unclear whether HGF has physiological and therapeutic functions during the progression of cholestasis. Using anti-HGF IgG or recombinant HGF in mice that had undergone bile duct ligation (BDL), we investigated the involvement of HGF in cholestasis-induced hepatitis. After the BDL surgery, HGF and c-Met mRNA levels transiently increased in livers during the progression of cholestatic hepatitis. When c-Met tyrosine phosphorylation was blocked in the livers of BDL-treated mice by anti-HGF IgG, hepatic dysfunction became evident, associated with the acceleration of hepatocyte necrosis and apoptosis. Inversely, administration of recombinant HGF into the mice led to the prevention of cholestasis-induced inflammation: HGF suppressed the hepatic expression of intracellular adhesion molecule-1 and neutrophil infiltration in BDL-treated mice. As a result, parenchymal necrosis was suppressed in the HGF-injected BDL mice. In addition, HGF supplement therapy reduced the number of apoptotic hepatocytes in cholestatic mice, associated with the early induction of Bcl-xL. The administration of HGF enhanced hepatic repair, via accelerating G1/S progression in hepatocytes. Our study showed that 1) upregulation of HGF production is required for protective mechanisms against cholestatic hepatitis and 2) enhancement of the intrinsic defense system by adding HGF may be a reasonable strategy to attenuate hepatic inflammation, necrosis, and apoptosis under bile-congestive conditions.

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Section: Discussionmentioning

confidence: 96%

“…In addition to necrotic events, hepatocyte apoptosis is notable under pathological conditions when the accumulation of bile acids is persistent (3,6,34): hydrophobic bile acids cause DNA fragmentation of hepatocytes in vitro (1). Furthermore, parenchymal apoptosis at 2 days post-BDL may also participate in the initial hepatic injury.…”

Section: Discussionmentioning

confidence: 99%

Antinecrotic and antiapoptotic effects of hepatocyte growth factor on cholestatic hepatitis in a mouse model of bile-obstructive diseases

Mizuno²,

Nakamura³

2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…After the initial peak on day 5, continuous proliferation was observed at a low level. The proportion of continuously proliferating hepatocytes is in the range of 1-3 per cent 5,14,26,27 . The present data suggest that hepatocellular proliferation in response to acute cholestatic liver injury can best be evaluated in the first week after BDL, whereas day 14 (or later) is appropriate for the evaluation of hepatocellular proliferation during chronic cholestasis.…”

Section: Discussionmentioning

confidence: 99%

Characterization of time-related changes after experimental bile duct ligation

Georgiev

Jochum

Heinrich

et al. 2008

British Journal of Surgery

207

184

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“…These findings suggest that NFB preferentially promotes DNA synthesis in the cholestatic liver. In addition, in cholestatic mice the immediateearly gene response remains intact as basal NFB and AP-1 DNA binding activity were increased and did not differ compared to controls [83].…”

Section: Regeneration In Liver Diseasementioning

confidence: 94%