Oral administration of polyamines ameliorates liver ischemia/reperfusion injury and promotes liver regeneration in rats

Abstract

Polyamines are essential for cell growth and differentiation. They play important roles in protection from liver damage and promotion of liver regeneration. However, little is known about the effect of oral exogenous polyamine administration on liver damage and regeneration. This study investigated the impact of polyamines (spermidine and spermine) on ischemia/ reperfusion injury (IRI) and liver regeneration. We used a rat model in which a 70% hepatectomy after 40 minutes of ischemia was performed to mimic the clinical condition of living donor partial liver transplantation (LT). Male Lewis rats were separated into 2 groups: a polyamine group given polyamines before and after operation as treatment and a vehicle group given distilled water as placebo. The levels of serum aspartate aminotransferase and alanine aminotransferase at 6, 24, and 48 hours after reperfusion were significantly lower in the polyamine group compared with those in the vehicle group. Polyamine treatment reduced the expression of several proinflammatory cytokines and chemokines at 6 hours after reperfusion. Histological analysis showed significantly less necrosis and apoptosis in the polyamine group at 6 hours after reperfusion. Sinusoidal endothelial cells were also well preserved in the polyamine group. In addition, the regeneration of the remnant liver at 24, 48, and 168 hours after reperfusion was significantly accelerated, and the Ki-67 labeling index and the expressions of proliferating cell nuclear antigen and phosphorylated retinoblastoma protein at 24 hours after reperfusion were significantly higher in the polyamine group compared with those in the vehicle group. In conclusion, perioperative oral polyamine administration attenuates liver IRI and promotes liver regeneration. It might be a new therapeutic option to improve the outcomes of partial LT. Liver Transplantation 22 1231-1244 2016 AASLD.Received January 24, 2016; accepted April 11, 2016. Liver transplantation (LT) is one of the most effective treatments for patients with end-stage liver disease and acute liver failure and has been widely accepted.(1,2) However, the shortage of donor organs is still a major problem for LT because of a limited pool of donors. Because of the donor organ shortage, living donor liver transplantation (LDLT) is a possible alternative and shows the most promising outcomes. (3)(4)(5) In LT, the liver graft is damaged during cold and warm ischemia time and blood reperfusion thereafter; this damage is called ischemia/reperfusion injury (IRI). Moreover, in LDLT, the first priority is donor safety, and in the clinical setting, the minimum-sized liver grafts that are as small as possible are selected.(6) In adult-to-adult LDLT, size mismatch between graft and recipient sometimes leads to primary graft nonfunction or dysfunction, a critical problem called "small-for-size syndrome," which occurs as a result of liver graft IRI and

Bolus Administration of Polyamines Boosts Effects on Hepatic Ischemia-Reperfusion Injury and Regeneration in Rats

“…Subsequently, activated Kupffer cells and T lymphocytes recruit neutrophils into the liver after reperfusion [19, 20]. Okumura et al [8] reported that the bolus administration of polyamines suppressed inflammatory cascades in the same rat model as the present study. Therefore, it is suggested that bolus administration of polyamines might have significant protective effects on the acute phase of IRI.…”

“…We also reported that oral polyamine administration by gastric tube alleviates IRI and promotes regeneration in inbred rats [8]. This showed the exogenous polyamines’ potential to contribute to improving the outcome of liver surgery, including liver transplantation.…”

“…1a). Whole blood was collected from the portal vein (PV) at the time points of 0, 1, 2, and 6 h. Concentrations of PUT, SPD, and SPM were measured using high-performance liquid chromatography as previously described [8] (Fig. 1a).…”

“…1c) [8, 14]. All surgical procedures were performed under inhalation anesthesia using 1.5% isoflurane.…”

“…Conventional morphological evaluation with hematoxylin and eosin (HE) staining was performed using the Suzuki score, which measures three parameters of hepatic IRI: sinusoidal congestion, vacuolization of hepatocyte cytoplasm, and parenchymal necrosis ( n = 6/group) [8, 14, 15]. …”