Liver Regeneration Is Suppressed in Small-for-Size Liver Grafts after Transplantation: Involvement of c-Jun N-terminal Kinase, Cyclin D1, and Defective Energy Supply

Zhong, Zhi; Schwabe, Robert F.; Kai, Yukihiro; He, Lihua; Yang, Liu; Bunzendahl, H.; Brenner, David A.; Lemasters, John J.

doi:10.1097/01.tp.0000228867.98158.d2

Cited by 63 publications

(102 citation statements)

References 54 publications

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“…Tissue damage due to the surgical process further decreases the amount of healthy remnant liver tissue leading to an additional reduction in functional liver capacity in the postoperative period [4,5] . This situation can lead to liver insufficiency and, ultimately, to liver failure and death [6][7][8] . Therefore, patients have to fulfil certain criteria, such as the absence of end-stage liver disease, in order to be eligible for extended hepatectomy [1] .…”

Section: Introductionmentioning

confidence: 99%

Extent of liver resection modulates the activation of transcription factors and the production of cytokines involved in liver regeneration

Sowa¹,

Best²,

Benkő³

et al. 2008

WJG

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AIM:To investigate the molecular events involved in liver regeneration following subtotal hepatectomy (SH) as previous studies have largely focused on partial hepatectomy (PH). METHODS:Male Wistar rats were subjected to 70% PH or 90% SH, respectively, and sacrificed at different times after surgery. Untreated and sham-operated animals served as controls. Serum and liver samples were obtained to investigate liver function, apoptosis (TUNEL assay) and transcription factors (NF-κB, Stat3; ELISA) or cytokines (HGF, TNF-a, IL-6, TGF-a, TGF-b; quantitative RT-PCR) involved in liver regeneration. RESULTS:Serum levels of ALT and AST in animals with 70% PH differed significantly from sham-operated and control animals. We found that the peak concentration 12 h after surgery returned to control levels 7 d after surgery. LDH was increased only at 12 h after 70% PH compared to sham. Bilirubin showed no differences between the sham and 70% resection. After PH, early NF-κB activation was detected 12 h after surgery (313.21 ± 17.22 ng/mL), while there was no activation after SH (125.22 ± 44.36 ng/mL) compared to controls (111.43 ± 32.68 ng/mL) at this time point. In SH, however, NF-κB activation was delayed until 24 h (475.56 ± 144.29 ng/mL). Stat3 activation was similar in both groups. These findings correlated with suppressed and delayed induction of regenerative genes after SH (i.e. TNF-a 24 h postoperatively: 2375 ± 1220 in 70% and 88 ± 31 in 90%; IL-6 12 h postoperatively: 2547 ± 441 in 70% and 173 ± 82 in 90%). TUNEL staining revealed elevated apoptosis rates in SH (0.44% at 24 h; 0.63% at 7 d) compared to PH (0.27% at 24 h; 0.15% at 7 d). CONCLUSION:The molecular events involved in liver regeneration are significantly influenced by the extent of resection as SH leads to suppression and delay of liver regeneration compared to PH, which is associated with delayed activation of NF-κB and suppression of proregenerative cytokines.

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Section: Introductionmentioning

confidence: 99%

Extent of liver resection modulates the activation of transcription factors and the production of cytokines involved in liver regeneration

Sowa¹,

Best²,

Benkő³

et al. 2008

WJG

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“…Although the initiating events in AILI have been attributed to reactive metabolite and protein adduct formation as well as glutathione depletion [2][3][4], the downstream signaling pathways controlling or promoting the severity of AILI have become of a great interest to many researchers [5][6][7][8][9][10][11][12][13][14]. One of these pathways involves JNK, which when activated is known to influence important cellular events, including alterations in gene expression [15], cell death [16], cellular proliferation and survival [17][18][19][20].Recent studies involving AILI in JNK2 −/− mice have led to conflicting results where JNK2 −/− mice were found to be either less susceptible [21] …”

mentioning

confidence: 99%

Protective role of c-Jun N-terminal kinase 2 in acetaminophen-induced liver injury

Bourdi

Korrapati²,

Chakraborty³

et al. 2008

Biochemical and Biophysical Research Communications

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Recent studies in mice suggest that stress-activated c-Jun N-terminal protein kinase 2 (JNK2) plays a pathologic role in acetaminophen (APAP)-induced liver injury (AILI), a major cause of acute liver failure (ALF). In contrast, we present evidence that JNK2 can have a protective role against AILI. When male C57BL/6J wild type (WT) and JNK2 −/− mice were treated with 300mg APAP/kg, 90% of JNK2 −/− mice died of ALF compared to 20% of WT mice within 48 h. The high susceptibility of JNK2 −/− mice to AILI appears to be due in part to deficiencies in hepatocyte proliferation and repair. Therefore, our findings are consistent with JNK2 signaling playing a protective role in AILI and further suggest that the use of JNK inhibitors as a potential treatment for AILI, as has been recommended by other investigators, should be reconsidered. KeywordsAcetaminophen; Cyclin D1; Hepatoprotection; c-Jun N-terminal kinase 2; JNK2; Liver injury; Proliferating cell nuclear antigen; Repair Overdose of APAP, a popular antipyretic and analgesic, is a leading cause of ALF resulting in approximately 1,800 deaths per year in the United States [1]. Although the initiating events in AILI have been attributed to reactive metabolite and protein adduct formation as well as glutathione depletion [2][3][4], the downstream signaling pathways controlling or promoting the severity of AILI have become of a great interest to many researchers [5][6][7][8][9][10][11][12][13][14]. One of these pathways involves JNK, which when activated is known to influence important cellular events, including alterations in gene expression [15], cell death [16], cellular proliferation and survival [17][18][19][20].Recent studies involving AILI in JNK2 −/− mice have led to conflicting results where JNK2 −/− mice were found to be either less susceptible [21] Animals and APAP treatmentSeven to 9 week-old male WT, JNK1 −/− and JNK2 −/− mice on a C57BL/6J background were purchased from Jackson Laboratories (Bar Harbor, ME). Mice were acclimated for at least 1 week to a 12-h light/dark cycle in a humidity and temperature-controlled, specific-pathogenfree environment in microisolator autoclaved cages. Mice were allowed autoclaved food and water ad libitum until experimental use. Before each study, mice were fasted overnight (14-16h; free access to water) to uniformly deplete hepatic GSH stores [23]. Food supplies were restored after intraperitoneal administration of APAP (300mg/kg in warm saline; 20ml/kg) or saline vehicle (20ml/kg). All maintenance of animals conformed to the guidelines for humane treatment set by the Association for Assessment and Accreditation for Laboratory Animal Care International's Guide for the Care and Use of Laboratory Animals and by the National Institutes of Health. Sera and tissue collectionBlood samples were collected and allowed to clot in microtainer serum separator tubes (Becton Dickinson and Co., Franklin Lakes, NJ) for approximately 2h at room temperature and then centrifuged. Serum was separated and used for ALT measurements. A por...

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“…After resection or injury the remaining hepatocytes enter into the G1 phase. Several previous studies demonstrated that cytokines, mainly TNF-α and IL-6, are involved in liver regeneration after partial hepatectomy [1,6,10,25] . TNF-α is recognized as a regulator of the initial phase of hepatic regeneration after liver resection and injury, given that it is able to increase the activity of DNA polymerase-α and the incorporation of [H3] thymidine into DNA in the liver cells of intact adult rats [26] .…”

Section: Discussionmentioning

confidence: 99%

“…Liver regeneration in small-for-size liver grafts and in subtotal hepatectomies may be suppressed, thereby increas-ing the morbidity and mortality in these situations [1,2] . The regenerative capacity of the liver has been known for a long time although the mechanisms of this complex physiological process are not completely understood.…”

Section: Introductionmentioning

confidence: 99%

Pentoxifylline improves liver regeneration through down-regulation of TNF-α synthesis and TGF-β1 gene expression

Martino¹,

Coelho

Kubrusly³

et al. 2012

WJGS

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AIM:To investigate the mechanism of pentoxifylline (PTX) improvement in liver regeneration. RESULTS:Rats were randomized into 4 groups: Control rats; Sham -sham-operation rats; Saline -70% hepatectomy plus saline solution; PTX -70% hepatectomy plus PTX. At 2 and 6 h after hepatectomy, aspartate aminotransferase, alanine aminotransferase, tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) serum and hepatic tissue levels were determined. Tumor growth factor (TGF)-β1 gene expression in liver tissue was evaluated 24 h after hepatectomy by quantitative reverse transcriptase polymerase chain reaction analysis. Proliferation was analyzed by mitotic index and proliferating cell nuclear antigen (PCNA) staining 48 h after hepatectomy. RESULTS:TNF-α and IL-6 serum levels increased at 2 and 6 h after hepatectomy. At 2 h after hepatectomy serum PTX was reduced but not hepatic levels of TNF-α and IL-6. A decrease in liver TGF-β1 gene expression and an increase in mitotic index and PCNA after hepatectomy were observed in the PTX treatment group in comparison to the saline group. CONCLUSION: PTX improves liver regeneration by a mechanism related to down regulation of TNF-α production and TGF-β1 gene expression.

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Liver Regeneration Is Suppressed in Small-for-Size Liver Grafts after Transplantation: Involvement of c-Jun N-terminal Kinase, Cyclin D1, and Defective Energy Supply

Abstract: Liver regeneration is stimulated in half-size grafts but suppressed in quarter-size grafts. Defective liver regeneration in small grafts is associated with an inhibition of the c-Jun N-terminal kinase/c-Jun and CyD1 pathways and compromised energy production.

Cited by 63 publications

References 54 publications

Extent of liver resection modulates the activation of transcription factors and the production of cytokines involved in liver regeneration

Extent of liver resection modulates the activation of transcription factors and the production of cytokines involved in liver regeneration

Protective role of c-Jun N-terminal kinase 2 in acetaminophen-induced liver injury

Pentoxifylline improves liver regeneration through down-regulation of TNF-α synthesis and TGF-β1 gene expression

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