Reperfusion stress induced during intermittent selective clamping accelerates rat liver regeneration through JNK pathway.
OBJECTIVE
Liver resection includes temporal vascular inflow occlusion resulting in ischemia/reperfusion injury in the remnant liver. Here, we developed a rat model of selective lobe occlusion to isolate reperfusion stress from ischemia and to analyze its effect on liver regeneration.


METHODS
Left lateral and median lobes of liver were either mobilized or subjected twice for 10min to ischemia followed by 5min reperfusion prior to resection while the regenerative lobes were only subjected to reperfusion.


RESULTS
Although intermittent reperfusion stress induced higher levels of serum transaminases, analysis of cell cycle regulators revealed accelerated regenerative response compared to standard partial hepatectomy. The G0/G1 transition occurred before tissue resection, as evidenced by c-fos, junB, and IL-6 induction. Following hepatectomy, Cyclin D1 up-regulation, G1/S transition, and cell division occurred earlier than normal. Unexpectedly, liver mobilization, a component of the clamping procedure, also resulted in earlier G1/S transition. The shortened G1-phase was driven by the c-Jun N-terminal Kinase pathway and was associated with an oxidative stress response as evidenced by the expression of inducible nitric oxide synthase.


CONCLUSIONS
Intermittent selective clamping of lobes to be resected induced reperfusion stress on remnant liver that was beneficial for liver regeneration, suggesting this procedure could be applied in clinical practice.
Duval
Hélène
H
Inserm U522, CHU Pontchaillou, Rue Henri Le Guilloux, Rennes, France.
Mbatchi
Sasse-Fanie
SF
Grandadam
Stéphane
S
Legendre
Claire
C
Loyer
Pascal
P
Ribault
Catherine
C
Piquet-Pellorce
Claire
C
Guguen-Guillouzo
Christiane
C
Boudjema
Karim
K
Corlu
Anne
A
D000818:Animals; D002455:Cell Division / Q000502:physiology; D019938:Cyclin D1 / Q000235:genetics; D016193:G1 Phase / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006498:Hepatectomy / Q000379:methods; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology*; D016192:Resting Phase, Cell Cycle / Q000502:physiology; D016196:S Phase / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology*; D013482:Superoxide Dismutase / Q000378:metabolism; D013525:Surgical Instruments; D000099156:Superoxide Dismutase 2
D019938:Cyclin D1; D051547:Heme Oxygenase-1; D015850:Interleukin-6; D048031:JNK Mitogen-Activated Protein Kinases; D052247:Nitric Oxide Synthase Type II; D016760:Proto-Oncogene Proteins c-fos; D050796:STAT3 Transcription Factor; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C530106:Ccnd1 protein, rat; C494088:Stat3 protein, rat; C496318:Nos2 protein, rat