The Roles Of Microcirculation Impairment And Cytokine Imbalance In Posthepatectomy Liver Failure And The Potential Treatment Strategies

Background Liver resection, also named as hepatectomy, is the treatment of Choice for most hepatobiliary malignancies. Posthepatectomy live failure (PHLF) is a feared complication and the main cause of mortality. In the rise of living donor liver transplantation, right liver donation predispose the donor to the risk of PHLF while left segmental donation leaves the recipient with the small-for-size syndrome (SFSS). PHLF is a complicated multi-factorial process. In this study, we investigated the characteristics of hemodynamics, transcriptome and inflammatory response in the process of PHLF, aiming to unravel its mechanism and treatment strategy.Methods Part 1:Rats subjected to hepatectomy of different extent (70%,85% and 90%) were monitored for survival and serum biochemistry. At each time points during and after the procedure, the portal vein flow and hepatic artery flow were monitored using Transonic Doppler and the hepatic sinusoidal microcirculation were tested using the laser sparkling contrast imaging (LSCI). Histology tests included the H&E, Oil Red O and Ki-67 staining. Electronic microscope was used to observe the ultrastructural change. Animal groups of different resection extents were compared using the above readouts. And the efficacy of associated perfusion preconditioning and early resection (APPER) was preliminarily tested. Part 2:Tissue samples from Part 1 were used for RNA microarray. Differentially expressed genes were identified and analyzed according to the GO and KEGG databases. Hierarchical clustering was also performed to display the distinguishable genes’ expression pattern among samples. Part 3:An observational body condition score after major hepatectomy in mice was established. Mice were divided into predetermined Death and Survival group. Inflammatory cytokines, including IL-6, TNF-α, MCP-1 and IL-1α, were serially monitored in the first postoperative 24h. Anti-IL-6 treatment for PHLF in mice was preliminarily validated.Results 90% hepatectomy is marginal for rat, with a 7d-survival of 43% and a marked elevation of liver enzymes. An abnormal hepatic hemodynamic change was observed with increased portal perfusion but declined sinusoidal microcirculation at 24h. H&E staining and electro-microscopy showed a more severe hepatocellular lipid accumulation in the extended hepatectomized animals. Hepatocelluar lipid droplets were frog egg-like, filling the cytoplasm and squeezing the hepatic sinusoid. APPER procedure could maintain sinusoidal microcirculation, attenuate hepatocellular injury and improve survivals. Part 2:RNA microarray showed that the metabolic pathways after massive hepatectomy were collectively shifting toward the inflammatory and regenerative response, with lipid metabolic pathways significantly up-regulated. Leading among the pathways was the PPAR signaling. Part 3:The body condition score could predict the posthepatectomy animal death with an accuracy of 97.3%. Cytokine monitoring showed that IL-6 led the first peak of inflammatory response at 6h. And anti-IL-6 treatment with a dose of 300ug/mouse at 3h could temporarily abrogate the over-inflammatory response and increase the survival by 30%.Conclusion Based on our data, we speculate that the early hepatic sinusoidal endothelial injury and the squeezing from the lipid droplet-filled hepatocytes may result in sinusoidal collapse and microcirculation failure, with some short-pass vessels opened under pressure. A good portion of hepatocyte would therefore be isolated from portal inflow. APPER would serve as a new protocoled liver surgery. An imbalanced stimulation of PPAR signaling would undermine the fatty acid β-oxidation and a supply of CPT-1 may address the lipid metabolic imbalance. IL-6 blockade in a controlled manner could abrogate the over-inflammatory response and improve survivals.