Effects of ischemic preconditioning in a pig model of large-for-size liver transplantation

Abstract

OBJECTIVE:In most cases of pediatric liver transplantation, the clinical scenario of large-for-size transplants can lead to hepatic dysfunction and a decreased blood supply to the liver graft. The objective of the present experimental investigation was to evaluate the effects of ischemic preconditioning on this clinical entity.METHODS:Eighteen pigs were divided into three groups and underwent liver transplantation: a control group, in which the weights of the donors were similar to those of the recipients, a large-for-size group, and a large-for-size + ischemic preconditioning group. Blood samples were collected from the recipients to evaluate the pH and the sodium, potassium, aspartate aminotransferase and alanine aminotransferase levels. In addition, hepatic tissue was sampled from the recipients for histological evaluation, immunohistochemical analyses to detect hepatocyte apoptosis and proliferation and molecular analyses to evaluate the gene expression of Bax (pro-apoptotic), Bcl-XL (anti-apoptotic), c-Fos and c-Jun (immediate-early genes), ischemia-reperfusion-related inflammatory cytokines (IL-1, TNF-alpha and IL-6, which is also a stimulator of hepatocyte regeneration), intracellular adhesion molecule, endothelial nitric oxide synthase (a mediator of the protective effect of ischemic preconditioning) and TGF-beta (a pro-fibrogenic cytokine).RESULTS:All animals developed acidosis. At 1 hour and 3 hours after reperfusion, the animals in the large-for-size and large-for-size + ischemic preconditioning groups had decreased serum levels of Na and increased serum levels of K and aspartate aminotransferase compared with the control group. The molecular analysis revealed higher expression of the Bax, TNF-alpha, I-CAM and TGF-beta genes in the large-for-size group compared with the control and large-for-size + ischemic preconditioning groups. Ischemic preconditioning was responsible for an increase in c-Fos, IL-1, IL-6 and e-NOS gene expression.CONCLUSION:Ischemia-reperfusion injury in this model of large-for-size liver transplantation could be partially attenuated by ischemic preconditioning.

Effect of remote ischemic preconditioning in the expression of IL-6 and IL-10 in a rat model of liver ischemia-reperfusion injury

“…Corroborating our findings, other studies using RIPC, but in different experimental models, also identified an elevation of IL-6 serum levels and IL-6 mRNA 15,16 .…”

Does a meso‐caval shunt have positive effects in a pig large‐for‐size liver transplantation model?

“…Furthermore, the e‐NOS gene was more highly expressed in the liver parenchyma of the LFS than the LFS+SHUNT group recipients. This gene is thought to be responsible for the production of nitric oxide, which is beneficial because it can lead to vasodilatation and the softening of ischemia–reperfusion lesion . Finally, these molecular findings may suggest an exacerbation of IRI promoted by the shunt, as gene expression is an immediate response and is a reflection of the low portal and arterial flow presented by SHUNT recipients one hour after reperfusion.…”

“…This situation can lead to reduced blood supply to the liver graft with higher incidences of graft dysfunction, acute rejection, and vascular complications. 1 IRI is one of the main mechanisms of graft injury in liver transplantation, [4][5][6] leading to complications such as poor graft function. 7 C-Fos and c-Jun are IEG that are activated precociously after IRI and regulate tissue responses to injury stimulation.…”

Preconditioning methods in the management of hepatic ischemia reperfusion‐ induced injury: Update on molecular and future perspectives

“…Earlier study on IPC has reported anti‐inflammatory action in liver transplants by inducing the expression level of peroxisomal proliferator‐activated receptor–α (PPAR–α) and adiponectin which inhibit NFκB inflammatory cascade . In addition, a suppressive effect on TNF–α expression and serum levels of interleukin‐6 (IL‐6) have been reported for the positive effects in liver graft survival …”