Somatostatin Therapy Improves Stellate Cell Activation And Early Fibrogenesis In A Preclinical Model Of Extended Major Hepatectomy

Simple Summary Liver resection is the best treatment for liver tumors; its clinical applicability, however, is limited by the mass and quality of the remnant liver. In this study, hepatic resections were performed in a pig model to define changes associated with sufficient and insufficient liver remnants. As well, somatostatin, a naturally occurring peptide hormone that exerts numerous largely inhibitory effects, was given in order to improve outcomes. We observed that extended major hepatectomy is associated with immediate changes in portal pressure leading to injury, stellate cell activation, collagen deposition, and cell death, all of which were improved with somatostatin therapy. This is one of few studies (potentially the first) describing collagen deposition as early as 24 h after extended major hepatectomy and implicating liver resection as potential cause for chronic liver injury. Liver resection treats primary and secondary liver tumors, though clinical applicability is limited by the remnant liver mass and quality. Herein, major hepatic resections were performed in pigs to define changes associated with sufficient and insufficient remnants and improve liver-specific outcomes with somatostatin therapy. Three experimental groups were performed: 75% hepatectomy (75H), 90% hepatectomy (90H), and 90% hepatectomy + somatostatin (90H + SST). Animals were followed for 24 h (N = 6) and 5 d (N = 6). After hepatectomy, portal 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 h, changes were observed in 90H associated with stellate cell activation and collapse of sinusoidal lumen. Collagen chain type 1 alpha 1 mRNA expression was higher, extracellular matrix width less, and percentage of collagen-staining areas greater at 24 h in 90H versus 75H and 90H + SST. After 5 d, remnant liver mass was higher in 75H and 90H + SST versus 90H, and Ki-67 immunostaining was higher in 90H + SST versus 75H and 90H. As well, more TUNEL-staining cells were observed in 90H versus 75H and 90H + SST at 5 d. Perioperative somatostatin modified portal pressure, injury, apoptosis, and stellate cell activation, stemming changes related to hepatic fibrogenesis seen in liver remnants not receiving treatment.