Hypoxia of the growing liver accelerates regeneration

Abstract

Background. After portal vein ligation of 1 side of the liver, the other side regenerates at a slow rate. This slow growth may be accelerated to rapid growth by adding a transection between the 2 sides, i.e., performing portal vein ligation and parenchymal transection. We found that in patients undergoing portal vein ligation and parenchymal transection, portal vein hyperflow in the regenerating liver causes a significant reduction of arterial flow due to the hepatic arterial buffer response. We postulated that the reduction of arterial flow induces hypoxia in the regenerating liver and used a rat model to assess hypoxia and its impact on kinetic growth. Methods. A rat model of rapid (portal vein ligation and parenchymal transection) and slow regeneration (portal vein ligation) was established. Portal vein flow and pressure data were collected. Liver regeneration was assessed in rats using computed tomography, proliferation with Ki-67, and hypoxia with pimonidazole and HIF-1a staining. Results. The rat model confirmed acceleration of regeneration in portal vein ligation and parenchymal transection as well as the portal vein hyperflow seen in patients. Additionally, tissue hypoxia was observed after portal vein ligation and parenchymal transection, while little hypoxia staining was detected after portal vein ligation. To determine if hypoxia is a consequence or an inciting stimulus of rapid liver regeneration, we used a prolylhydroxylase blocker to activate hypoxia signaling pathways in the slow model. This clearly accelerated slow to rapid liver regeneration. Inversely, abrogation of hypoxia led to a blunting of rapid growth to slow growth. The topical application of prolyl-hydroxylase inhibitors on livers in rats induced spontaneous areas of regeneration. Conclusion. This study shows that pharmacologically induced hypoxic signaling accelerates liver regeneration similar to portal vein ligation and parenchymal transection. Hypoxia is likely an accelerator of liver regeneration. Also, prolyl-hydroxylase inhibitors may be used to enhance liver regeneration pharmaceutically. Background. After portal vein ligation of 1 side of the liver, the other side regenerates at a slow rate. This slow growth may be accelerated to rapid growth by adding a transection between the 2 sides, i.e., performing portal vein ligation and parenchymal transection. We found that in patients undergoing portal vein ligation and parenchymal transection, portal vein hyperflow in the regenerating liver causes a significant reduction of arterial flow due to the hepatic arterial buffer response. We postulated that the reduction of arterial flow induces hypoxia in the regenerating liver and used a rat model to assess hypoxia and its impact on kinetic growth. Methods. A rat model of rapid (portal vein ligation and parenchymal transection) and slow regeneration (portal vein ligation) was established. Portal vein flow and pressure data were collected. Liver regeneration was assessed in rats using computed tomography, proliferation with Ki-6...

Serial Assessment of Growth Factors Associated with Liver Regeneration in Patients Operated with Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy

“…This appears to be a paradox, but it might represent a response to apoptosis in the deportalized liver. Schadde et al [25] recently described that tissue hypoxia in the FLR after ALPPS lead to a higher degree of regeneration, but this does not necessarily explain our findings in the deportalized lobe. Another possible explanation is that the biopsies collected at stage 2 were taken 7 days after baseline biopsies at stage 1.…”

Impaired liver regeneration after hepatectomy and bleeding is associated with a shift from hepatocyte proliferation to hypertrophy

“…(15) demonstrated that in hepatocytes that were subjected to hypoxia and reoxygenation, HIF-1α targets the peroxisome rather than the nucleus, where it colocalizes with von Hippel-Lindau and the HIF hydroxylases. Nevertheless, in a rat model of portal ligation combined with parenchymal transection, Schadde et al (37) showed that different levels of hypoxia may play a critical role in liver regeneration through HIF-1α. In our study, rats subjected to PHx and bleeding demonstrated elevated HIF-1α both in the cytoplasm and the nuclei (Fig.…”

Hypoxia protects the liver from Small For Size Syndrome: A lesson learned from the associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure in rats

“…The contribution of the parenchymal transection to accelerated and enhanced hypertrophy is further underlined by the observation that in‐situ split has been used as a rescue technique for patients whose liver fails to hypertrophy after portal vein occlusion . Clinical studies document that ALPPS procedure causes an immediate and steep rise of the portal pressure and flow into the liver remnant accompanied by a compensatory arterial constriction (HABR) . In experimental models, in ALPPS step I, but not in portal vein occlusion alone, the HABR was associated with hypoxia …”