Simulated model of RAPID concept: highlighting innate inflammation and liver regeneration

• Published in: BJS open Vol. 4; no. 5; pp. 893 - 903
• Main Authors: Shi, J. H., Yan, X., Zhang, S. J., Line, P. D.
• Format: Journal Article
• Language: English; Norwegian
• Published: Chichester, UK John Wiley & Sons, Ltd 01.10.2020; Oxford University Press
• Subjects: Bone marrow; HPB; Ischemia; Kinases; Liver; Original; Surgery; Tumors; Veins & arteries; United States > US; China; California
• ISSN: 2474-9842; 2474-9842
• DOI: 10.1002/bjs5.50322

Background The resection and partial liver segment II/III transplantation with delayed total hepatectomy (RAPID) concept is a novel transplantation technique for removal of non‐resectable liver tumours. The aim of this study was to establish a simulated RAPID model to explore the mechanism involved in the liver regeneration. Methods A RAPID model was created in rats involving cold ischaemia and reperfusion of the selected future liver remnant (FLR), portal vein ligation, followed by resection of the deportalized lobes in a second step. Histology, liver regeneration and inflammatory markers in RAPID‐treated rats were compared with those in controls that underwent 70 per cent hepatectomy with the same FLR size. The effects of interleukin (IL) 6 and macrophage polarization on hepatocyte viability were evaluated in an in vitro co‐culture system of macrophages and BRL hepatocytes. Results The survival rate in RAPID and control hepatectomy groups was 100 per cent. The regeneration rate was higher in the RAPID‐treated rats, with higher levels of IL‐6 and M1 macrophage polarization (P < 0·050). BRL hepatocytes co‐cultured with M1 macrophages showed a higher proliferation rate through activation of the IL‐6/signal transducer and activator of transcription 3/extracellular signal‐regulated kinase pathway. This enhancement of proliferation was inhibited by tocilizumab or gadolinium trichloride (P < 0·050). Conclusion The surgical model provides a simulation of RAPID that can be used to study the liver regeneration profile. Surgical Relevance The mechanisms sustaining liver regeneration are a relevant field of research to reduce the ‘small for size’ liver syndrome when the future liver remnant is not adequate. Several surgical strategies have been introduced both for liver resection and transplant surgery, mostly related to this issue and to the scarcity of grafts, among these the RAPID concept involving the use of an auxiliary segment II/III donor liver that expands to a sufficient size until a safe second‐stage hepatectomy can be performed. Understanding the mechanisms and pitfalls of the liver regeneration profile may help in tailoring surgical strategies and in selecting patients. In this experimental model the authors investigated liver histology, regeneration and inflammatory markers in RAPID‐treated rats. Antecedentes La asociación de la resección y el trasplante de los segmentos 2/3 hepáticos antes de completar, de forma diferida, una hepatectomía total (Resection And Partial Liver Segment 2/3 Transplantation With Delayed Total Hepatectomy, RAPID) es una nueva técnica de trasplante que permite extirpar tumores hepáticos inicialmente no resecables. El objetivo de este estudio fue simular un modelo RAPID para estudiar los mecanismos involucrados en la regeneración hepática. Métodos Se desarrolló un modelo RAPID en ratas mediante isquemia fría y reperfusión del futuro remanente hepático (future liver remnant, FLR) y ligadura de la vena porta, seguido de resección de los lóbulos deportalizados (ligadura portal previa). Se comparó la histología, la regeneración hepática y los marcadores inflamatorios en las ratas tratadas con RAPID frente a un grupo control, en el que se realizó una hepatectomía del 70% del mismo tamaño del FLR. Se evaluaron los efectos sobre la IL‐6 y la polarización de los macrófagos para la viabilidad hepatocitaria mediante un sistema de cocultivo in vitro de macrófagos y hepatocitos BRL. Resultados La tasa de supervivencia tras el modelo RAPID y en la hepatectomía control fue del 100%. La tasa de regeneración fue mayor en las ratas tratadas con RAPID con niveles más elevados de IL‐6 y mayor polarización de macrófagos M1 (P < 0,05). Los hepatocitos BRL cocultivados con macrófagos M1 mostraron una tasa de proliferación mayor mediada a través de la activación de la vía IL‐6/STAT3/ERK, mientras que tocilizumab o GdCl3 inhibieron la respuesta proliferativa (P < 0,05). Conclusión Este modelo quirúrgico proporciona una aproximación a la técnica RAPID que permite estudiar la regeneración hepática. The mechanism of RAPID‐associated liver regeneration and its regulation remains unclear. A RAPID model in rats was developed involving cold ischaemia and reperfusion of the selected future liver remnant, portal vein ligation of the remaining segments during step I, and resection of the deportalized lobes during step II. Enhanced liver regeneration following RAPID was observed and may be related to M1 macrophages through the interleukin 6 pathway. ML, median lobe; LLL, left lateral lobe; RL, right lobe; CL, caudate lobe. RAPID model and liver regeneration.