Liver failure after extended hepatectomy in mice is mediated by a p21-dependent barrier to liver regeneration
| Autor: | Jae Hwi Jang, Oliver Tschopp, Achim Weber, Andreas Rickenbacher, Christian E. Oberkofler, Bostjan Humar, Simon M. Schultze, Kuno Lehmann, Pierre-Alain Clavien, Rolf Graf, Christoph Tschuor, Dimitri A. Raptis |
|---|---|
| Přispěvatelé: | University of Zurich |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
medicine.medical_treatment 10265 Clinic for Endocrinology and Diabetology 610 Medicine & health Biology medicine.disease_cause 03 medical and health sciences Mice 0302 clinical medicine Cholestasis 10049 Institute of Pathology and Molecular Pathology medicine Animals Hepatectomy 2715 Gastroenterology 030304 developmental biology Cell Proliferation 10217 Clinic for Visceral and Transplantation Surgery Mice Knockout 0303 health sciences Hepatology Cell Cycle Forkhead Box Protein M1 Gastroenterology Forkhead Transcription Factors Organ Size Cell cycle medicine.disease Liver regeneration Proliferating cell nuclear antigen Liver Regeneration Mice Inbred C57BL Disease Models Animal medicine.anatomical_structure Liver 030220 oncology & carcinogenesis Hepatocyte Knockout mouse Immunology Cancer research biology.protein 2721 Hepatology Oxidative stress Liver Failure |
| Zdroj: | Gastroenterology GASTROENTEROLOGY |
| Popis: | Background & Aims Extended liver resection leads to hepatic failure because of a small remnant liver volume. Excessive parenchymal damage has been proposed as the principal cause of this failure, but little is known about the contribution of a primary deficiency in liver regeneration. We developed a mouse model to assess the regenerative capacity of a critically small liver remnant. Methods Extended (86%) hepatectomy (eHx) was modified to minimize collateral damage; effects were compared with those of standard (68%) partial hepatectomy (pHx) in mice. Markers of liver integrity and survival were evaluated after resection. Liver regeneration was assessed by weight gain, proliferative activity (analyses of Ki67, proliferating cell nuclear antigen, phosphorylated histone 3, mitosis, and ploidy), and regeneration-associated molecules. Knockout mice were used to study the role of p21. Results Compared with pHx, survival of mice was reduced after eHx, and associated with cholestasis and impaired liver function. However, no significant differences in hepatocyte death, sinusoidal injury, oxidative stress, or energy depletion were observed between mice after eHx or pHx. No defect in the initiation of hepatocyte proliferation was apparent. However, restoration of liver mass was delayed after eHx and associated with inadequate induction of Foxm1b and a p21-dependent delay in cell-cycle progression. In p21 -/- mice, the cell cycle was restored, the gain in liver weight was accelerated, and survival improved after eHx. Conclusions Significant parenchymal injury is not required for liver failure to develop after extended hepatectomy. Rather, liver dysfunction after eHx results from a transient, p21-dependent block before hepatocyte division. Therefore, a deficiency in cell-cycle progression causes liver failure after extended hepatectomy and can be overcome by inhibition of p21. |
| Databáze: | OpenAIRE |
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