Portal vein stenosis preconditioning of living donor liver in swine: early mechanisms of liver regeneration and gain of hepatic functional mass

Abstract

To reduce the morbidity and mortality risk for the donor in living donor liver transplantation (LDLT), we previously identified 20% left portal vein (LPV) stenosis as an effective preconditioning method to induce cell proliferation in the contralateral lobe without downstream ipsilateral atrophy. In this study, we report the pathways involved in the first hours after preconditioning and investigate the changes in liver volume and function. Fourteen pigs were used this study. Five pigs were used to study the genetic, cellular and molecular mechanisms set up in the early hours following the establishment of our preconditioning. The remaining nine pigs were equally divided into three groups: sham-operated animals, 20% LPV stenosis, and 100% LPV stenosis. Volumetric scanning and 99 mTc-Mebrofenin hepatobiliary scintigraphy were performed before preconditioning and 14 days after to study morphological and functional changes in the liver. We demonstrated that liver regeneration triggered by 20% LPV stenosis in the contralateral lobe involves TNF-α, IL-6, and inducible nitric oxide synthase 2 by means of STAT3 and hepatocyte growth factor. We confirmed that our preconditioning was responsible for an increase in the total liver volume. Finally, we demonstrated that this volumetric gain was associated with an increase in hepatic functional capacity. NEW & NOTEWORTHY We describe a new preconditioning method for major hepatectomy that is applicable to hepatectomy for donation. We identified 20% left portal vein stenosis as effective preconditioning that is capable of inducing cell proliferation in the contralateral lobe without the downstream ipsilateral atrophy. In this study, we report the pathways involved in the first hours following preconditioning, and we confirm that 20% left portal vein stenosis is responsible for an increase in the functional capacity and total liver volume in a porcine model.

Surgical Models of Liver Regeneration in Pigs: A Practical Review of the Literature for Researchers

“…Chen et al [43] performed a bio-artificial liver treatment using 200 g of spheroid reservoir bio-artificial liver (SRBAL) to promote liver regeneration after 85% hepatectomy, observing an increment in IL6 and TGFβ values, but not in TNFα. Instead, Brige et al [45] demonstrated that portal vein stenosis preconditioning could determine higher values of IL6, IL10, HGF, and TNFα, even without liver resection.…”

“…Nine articles evaluated liver regeneration as a response to PVE, PVL, and ALPPS. In particular, Asencio et al described how a PVE performed 24 h before a 90% hepatectomy could affect the regenerative process [49], while Brige et al used PVE to generate a 100% stenosis to be compared to a partial 20% stenosis of the portal vein [45]. Gaillard et al proposed a new technique, making a comparison between standard permanent PVE and reversible PVE through an absorbable material, finding that repeated reversible PVE (with a second PVE treatment 14 days after the previous one) could boost liver hypertrophy more than the other "one-shot" treatments [29].…”

“…Only two studies considered a hepatotoxic pre-treatment using retrorsine [42] or carbon tetrachloride (CCl4) and alcohol [56]. Regarding the PH, sixteen experiments studied liver regeneration in response to liver resection without any additional procedures, while 20 studies evaluated how the liver regenerative capacity was influenced by SCA [30][31][32]39,41,44,51,[66][67][68], IRI [30,32,39,41,53,61,63,66], PVM [34,45,48,58], PVE [49], liver scaffold application [31,33], bio-artificial liver treatment [43], and application of terlipressin and octreotide [64,65]. The caudate lobe was always preserved.…”

“…Bucur et al [48] and Gregoire et al [58] increased liver regeneration by applying a vascular silicon ring around the PV or the left PV, with a reduction of 20% and 45% of portal blood flow, respectively. Brige et al [45] studied the 20% left PV flow reduction through a silk thread around the vessel. Instead, Xue et al [69] used a silk thread to narrow the PV circumference by 1/3 and 1/2, to establish acute liver failure without liver resection.…”

Desarrollo de un modelo animal de atrofia-hipertrofia y daño hepático tras radioembolización lobar con YTRIO-90 en conejos

“…Existen modelos experimentales de PVL también en animales grandes como el llevado a cabo en 2018, en un modelo porcino. Este modelo objetivó, a través de análisis genéticos, moleculares y celulares, que la estenosis del 20 % de la vena porta izquierda desencadenaba la fase de preparación de la regeneración hepática en el lóbulo contralateral e involucraba a TNF-α, IL-6 y óxido nítrico sintasa 2, responsables de un aumento en la capacidad funcional y en el volumen hepático total [98]. En otro modelo porcino publicado en el mismo año, se observó que la administración de citoquinas (IL-6 y TNF-α), un anticuerpo monoclonal contra TGF-β1 (MAB TGF-β1) y células madre mesenquimales en las ramas portales no ocluidas inmediatamente tras PVL, inducía un crecimiento más rápido del volumen del FLR [99].…”