Somatostatin Therapy Improves Stellate Cell Activation and Early Fibrogenesis in a Preclinical Model of Extended Major Hepatectomy

Abstract

Background: Liver resection is effective treatment for primary and secondary liver tumors, though clinical applicability is limited by remnant liver mass and quality. Aims: Perform major hepatic resections in pigs to define changes associated with sufficient and insufficient remnants and improve liver-specific outcomes through continuous somatostatin infusion. Methods: Three experimental groups were performed: 75% hepatectomy (75H), 90% hepatectomy (90H), and 90% hepatectomy with somatostatin (90H+SST). In each group, animals were followed for 24 hours (N=6) and 5 days (N=6). Results: After hepatectomy, portal venous pressure gradient was higher in 90H versus 75H and 90H+SST (8[3-13] mmHg vs. 4[2-6] mmHg and 4[2-6] mmHg, respectively, P <0.001). After 24 hours, changes were observed in 90H associated with stellate cell activation and collapse of sinusoidal lumen (area 23.5±3.6% 90H vs. 31.1±3.5% 75H, P <0.001, and 30.9±4.3% 90H+SST, P=0.008). Collagen chain type 1 alpha 1 mRNA expression was higher, extracellular matrix width less, and percentage of collagen-staining areas greater at 24 hours in 90H versus 75H and 90H+SST.After 5 days, remnant liver mass was higher in 75H and 90H+SST versus 90H (469±33 g and 463±79 g vs. 313±107, respectively, P=0.003), and Ki-67 immunostaining was higher in 90H+SST versus 75H and 90H (10±7 high-power field-1 vs. 2±2 high-power field-1 and 5±6 high-power field-1, respectively, P<0.001). More TUNEL-staining cells were observed in 90H versus 75H and 90H+SST at 5 days. Conclusions: Perioperative somatostatin modified portal pressure, injury, apoptosis, and hepatic stellate cell activation, stemming early changes related to hepatic fibrogenesis seen in liver remnants not receiving treatment. Funding: Research was supported by FIS Grant 15/01092 from the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacion, Spain. Amelia J. Hessheimer was supported by the “Ajut Josep Font” from the Hospital Clinic Barcelona. Lilia Martinez de la Maza was supported by the Fundacio Catalana de Trasplantament. Declaration of Interest: Amelia J. Hessheimer and Constantino Fondevila have received research funding and consultancy fees from Guanguong Shunde Innovative Design Institute, Guangdong, China. The remainder of the authors have nothing to declare. Ethical Approval: The University of Barcelona Animal Experimentation Unit is authorized by the Catalan Department of Agriculture, Husbandry, and Fisheries (authorization number B9900020), registered in the General Registry of Livestock Facilities (ES080190036536), and accredited by the International Standards Organization (ISO 9001:2015). Animals were cared for according to the guidelines of the Catalan Department of the Environment Commission on Animal Experimentation and University of Barcelona Committee on Ethics in Animal Experimentation, which approved the study protocol.