Severe Preservation Injury Induces Il-6/STAT3 Activation with Lack of Cell Cycle Progression After Partial Liver Graft Transplantation

Abstract

Partial liver graft transplantation is a surgical advance developed to overcome severe donor shortage. Survival of these grafts involves recovery from cold ischemia and reperfusion (CIR) injury, immediate regeneration and maintenance of function. Here we examined the outcome of partial liver grafts in comparison to whole grafts following CIR injury.Lewis rats subjected to orthotopic liver transplantation (OLT) with whole grafts preserved in Viaspan® were compared to rats receiving 50% and 30% grafts. Outcome was analyzed by survival and regeneration.Transplantation was associated with 100% survival for all grafts, whereas 16 h preservation resulted in 100%, 20% and 0% survival in animals receiving whole, 50% and 30% grafts, respectively. CIR induced increased IL-6 levels in 50% and 30% grafts, and activation of STAT3. Cell cycle progression (cyclin D1) and regeneration (BrdU) was initiated in all livers preserved for 1 or 8 h, but not in partial grafts preserved for 16 h.In conclusion, partial grafts recover from CIR injury through similar molecular pathways to whole grafts. Partial grafts with severe injury fail to achieve cellular proliferation despite the early initiating signals. This failure could be attributed to the impaired ability of the parenchyma to respond to initiating signals for regeneration.

Small‐for‐Size Syndrome After Partial Liver Transplantation: Definition, Mechanisms of Disease and Clinical Implications

“…But there is a lower limit of remnant liver where regeneration fails, an effect supported by more recent work in small-for-size mouse liver transplantation (8). Furthermore, warm ischemia (19) as well as cold ischemia (7) have been shown to impair regeneration after partial liver transplantation by interfering with the production of interleukin-6 (IL-6) and tumor necrosis factor a (TNFa) and/or defective progression from the IL-6 signaling pathway to cellular proliferation (20). This could be important for split grafts from cadaveric donors where longer cold ischemia occurs.…”

Improving Research Practice in Rat Orthotopic and Partial Orthotopic Liver Transplantation: A Review, Recommendation, and Publication Guide

“…Table 1 shows the numerous creative technical solutions elaborated to optimize graft rearterialization in rat OLT and P-OLT [8,12,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39]. …”

Liver I/R injury is improved by the arginase inhibitor, Nω-hydroxy-nor-l-arginine (nor-NOHA)

“…Transient episodes of hepatic ischemia occur during solid organ transplantation, trauma, hypovolemic shock, and elective liver resection, when inflow occlusion or total vascular exclusion is used to minimize blood loss. The pathophysiology of liver I/R injury includes both direct cellular damage as the result of the ischemic insult as well as delayed dysfunction and damage resulting from activation of inflammatory pathways (3,6,8,21,26,29). The injury that results from I/R after liver transplantation contributes to primary nonfunction in ϳ5-10% of liver grafts and delayed graft function in 15-30% of cases (9,30).…”