https://scholars.lib.ntu.edu.tw/handle/123456789/457885
標題: | Perturbations in ataxia telangiectasia mutant signaling pathways after drug-induced acute liver failure and their reversal during rescue of animals by cell therapy | 作者: | Bandi S. Joseph B. Berishvili E. Singhania R. YAO-MING WU Cheng K. Gupta S. |
公開日期: | 2011 | 出版社: | Elsevier Inc. | 卷: | 178 | 期: | 1 | 起(迄)頁: | 161-174 | 來源出版物: | American Journal of Pathology | 摘要: | Superior insights into molecular mechanisms of liver failure, which are not fully understood, will help strategies for inducing liver regeneration. We examined hepatotoxic mechanisms in mice homozygous for the severe combined immune deficiency mutation in the protein kinase, DNA-activated, catalytic polypeptide. Mice were treated with rifampicin, phenytoin, and monocrotaline. The ensuing acute liver failure was characterized by serological, histological, and mRNA studies. Subsequently, we studied whether transplantation of hepatocytes could rescue animals with liver failure. We found extensive liver damage in these animals, with mortality over several days. The expression of multiple hepatic genes was rapidly altered, including those representing pathways in oxidative/metabolic stress, inflammation, DNA damage-repair, and ataxia telangiectasia mutant (Atm) signaling pathways. This led to liver cell growth arrest involving cyclin-dependent kinase inhibitor 1A. Transplantation of hepatocytes with microcarriers in the peritoneal cavity efficiently rescued animals with liver failure. Molecular abnormalities rapidly reversed, including in hepatic Atm and downstream signaling pathways; and residual hepatocytes overcame cyclin-dependent kinase inhibitor 1A-induced cell growth arrest. Reseeding of the liver with transplanted hepatocytes was not required for rescue because native hepatocytes overcame cell growth-arrest to regenerate the liver. This likely resulted from paracrine signaling from hepatocytes in the peritoneal cavity. We concluded that Atm signaling played critical roles in the pathological features of liver failure. These studies should help redirect examination of pathophysiologic and therapeutic mechanisms in liver failure. Copyright ? 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-79251501338&doi=10.1016%2fj.ajpath.2010.11.001&partnerID=40&md5=8e50e1cbea7aa606d7ff722c19e1e86e https://scholars.lib.ntu.edu.tw/handle/123456789/457885 |
ISSN: | 0002-9440 | DOI: | 10.1016/j.ajpath.2010.11.001 | SDG/關鍵字: | ATM protein; caspase 8; chaperonin; cyclin D1; cyclin dependent kinase inhibitor 1A; cyclin G1; cytochrome P450 1B1; cytochrome P450 2A5; cytochrome P450 2B9; cytochrome P450 3A11; cytochrome P450 3A4; early growth response factor 1; Fas ligand; glutathione peroxidase 2; glutathione transferase; heme oxygenase 1; interleukin 18; interleukin 1beta; interleukin 1beta converting enzyme; interleukin 6; lipocortin 5; monocrotaline; phenytoin; protein bcl 2; protein kinase; rifampicin; uracil DNA glycosidase; acute liver failure; animal cell; animal experiment; animal model; animal tissue; article; cell cycle arrest; cell growth; cell therapy; cell transplantation; controlled study; DNA damage; DNA repair; gene expression regulation; gene mutation; histopathology; human; liver cell; liver injury; metabolic stress; mouse; nonhuman; oxidative stress; peritoneal cavity; priority journal; real time polymerase chain reaction; signal transduction |
顯示於: | 醫學系 |
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