Resumen

Background: The regenerative capacity of the liver is critical for proper responses to injury. Fibrin extracellular matrix (ECM) deposition is a common response to insult and contributes to inflammatory liver injury. However, the role of this matrix in hepatic regeneration has not been determined. Objective: The purpose of this study was first to determine the role of fibrin ECM in hepatic regeneration followed by the role of the fibrin-binding α_vβ₃ integrin in mediating this effect. Material and methods: C57Bl/6J(WT) or PAI-1 knockout (KO) mice underwent 70% partial hepatectomy (PHx); plasma and histologic indices of regeneration were determined, as well as expression of key genes involved in hepatic regeneration. Results PHx promoted transient fibrin depositionby activating coagulation and concomitantly decreasing fibrinolysis. Inhibiting fibrin deposition, either by blocking thrombin (hirudin) inWT mice or by knocking out PAI-1, was associated with a decrease in hepatocyte proliferation after PHx. This strongly suggested a role for fibrin ECM in liver regeneration. To investigate if α_vβ₃ integrin mediates this action, we tested the effects of the anti- α_vβ₃ cyclic peptide RGDfV in animals after PHx. As was observed with inhibition of fibrin deposition, competitive inhibition of α_vβ₃ integrin delayed regeneration after PHx, while not affecting fibrin deposition. These effects of RGDfV correlated with impaired angio-genesis and STAT3 signaling, as well as transient endothelial dysfunction. In conclusion, these data suggest that α_vβ₃ integrin plays an important role in coordinating hepatocyte division during liver regeneration after PHx via crosstalk with fibrin ECM.

Palabras clave: Liver regeneration fibrin(ogen) extracellular matrix alpha v beta 3 endothelial cell damage.

2016-10-21   |   238 visitas   |   Evalua este artículo 0 valoraciones

Vol. 15 Núm.5. Septiembre-Octubre 2016 Pags. 762-772 Ann Hepatol 2016; 15(5)