Abstract
Intermittent clamping of the portal trial is an effective method to avoid excessive blood loss during hepatic resection, but this procedure may cause ischemic damage to liver. Intermittent selective clamping of the lobes to be resected may represent a good alternative as it exposes the remnant liver only to the reperfusion stress. We compared the effect of intermittent total or selective clamping on hepatocellular injury and liver regeneration. Entire hepatic lobes or only lobes to be resected were subjected twice to 10 min of ischemia followed by 5 min of reperfusion before hepatectomy. We provided evidence that the effect of intermittent clamping can be damaging or beneficial depending to its mode of application. Although transaminase levels were similar in all groups, intermittent total clamping impaired liver regeneration and increased apoptosis. In contrast, intermittent selective clamping improved liver protein secretion and hepatocyte proliferation when compared with standard hepatectomy. This beneficial effect was linked to better adenosine-5′-triphosphate (ATP) recovery, nitric oxide production, antioxidant activities and endoplasmic reticulum adaptation leading to limit mitochondrial damage and apoptosis. Interestingly, transient and early chaperone inductions resulted in a controlled activation of the unfolded protein response concomitantly to endothelial nitric oxide synthase, extracellular signal-regulated kinase-1/2 (ERK1/2) and p38 MAPK activation that favors liver regeneration. Endoplasmic reticulum stress is a central target through which intermittent selective clamping exerts its cytoprotective effect and improves liver regeneration. This procedure could be applied as a powerful protective modality in the field of living donor liver transplantation and liver surgery.
Highlights
This phenomenon provokes a rapid and severe decline in high-energy phosphate compound levels, generalized cell membrane depolarization as well as a large increase in intracellular Ca2 þ concentration accompanied by Ca2 þ depletion from the endoplasmic reticulum (ER)
Liver regeneration following either an intermittent selective clamping of the lobes to be resected prior hepatectomy, subjecting the remnant liver only to reperfusion stress (RPH), or an intermittent clamping of the entire hepatic pedicle (TCPH) before resection, subjecting the whole liver to I/R stress, was first evaluated. Both surgical procedures were compared with standard partial hepatectomy (PH) or lobe exteriorization and mobilization without clamping followed (NCPH) or not (SHAM) by a resection (Figure 1)
Quantification of the mitotic index, percentage of hepatocyte 5-bromo-20deoxyuridine (BrdU) incorporation and proliferating cell nuclear antigen (PCNA) expression at different times after resection showed that liver regeneration was impaired in the TCPH group (Figures 2a–d)
Summary
This phenomenon provokes a rapid and severe decline in high-energy phosphate compound levels, generalized cell membrane depolarization as well as a large increase in intracellular Ca2 þ concentration accompanied by Ca2 þ depletion from the endoplasmic reticulum (ER) This mobilization of Ca2 þ stores from ER plays a significant role in modulating the mitochondrial Ca2 þ responses and the susceptibility of hepatocytes to apoptotic signals.[5,6]. When injury is excessive and ER function unrestored, the ER stress signal transduction pathways induce cell death through induction of transcription factor C/EBP-homologous protein (CHOP).[15,18] We have previously reported, using an original rat model of intermittent selective clamping[19] of the hepatic lobes to be resected, that short intermittent reperfusion stress induces mild liver injury and accelerates the regenerative response compared with a partial hepatectomy without clamping via JNK activation.[19] intermittent clamping is being widely used in the clinical setting, experiments evaluating underlying mechanisms of action, its effect on ER function, hepatic protein synthesis, energetic metabolism restoration, nitric oxide (NO) production and antioxidant activities after hepatectomy, are lacking. This better liver recovery after resection is linked to greater maintenance of antioxidant activities, enhanced preservation and
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