Matrix metalloproteinase-9 after the cold ischemia/reperfusion injury and/or shear stress with portal hypertension: an overview

Abstract

Cold ischemia/warm reperfusion injury (CIWRI) during liver transplantation (LT) and shear stress with portal hypertension (SSPH) associated with hepatectomy are critical issues [1, 2], and has been confirmed from the early postoperative period [3, 4]. They trigger a liver regeneration cascade, but can also cause fatal damage in liver remnants/ grafts. Matrix metalloproteinases (MMPs) are a family of enzymes capable of degrading the constituents of the extracellular matrix and the basement membrane. A total of 28 MMPs have been identified so far. MMP-9 is especially important for liver regeneration, and many studies have focused on the role of MMP-9 after liver surgery, including LT with small-for-size grafts (SFSGs) [3–5]. Although inhibition of MMP-9 attenuated acute graft injury in the drastic SFSG model (a rat LT model with a 25 % graft) [5], the behavior of MMP-9 in CIWRI and/or SSPH is still unclear. We herein investigated the behaviors of MMPs during the early postoperative period in various clinically relevant conditions which clearly showed liver damage in the conventional liver test. For these studies, Lewis rats were divided into five groups according to the surgical treatments: (1) laparotomy, (2) temporary clamping for 15 min (Pringle maneuver) as temporary inflow occlusion, (3) orthotopic liver transplantation (OLT) with a wholeliver graft (100 % OLT), (4) partial hepatectomy without temporal inflow occlusion (60 % hepatectomy) and (5) split orthotopic liver transplantation (SOLT) with SFSG (40 % SOLT). In this study, we employed a cold ischemia time of 3 h at 4 C in 100 % OLT (3) and 40 % SOLT (5), although this term of cold preservation is considered to be minimal in the rat liver transplantation model. Liver samples were collected 6 h after surgery (n = 4 in each group). Rat liver transplantation requires skillful techniques, and surgical issues cannot be ignored because they will affect the results. The anhepatic phase is a key for a successful surgery, and this phase in all recipients was \20 min in this study. We also omitted samples if any complications are observed at autopsy. Western blotting for MMP-9 expression and zymography for MMP-9 activity were performed. The expression of MMP-9 was not significantly different following temporary clamping, 100 % OLT and 60 % hepatectomy compared with the levels following laparotomy, T. Hori (&) S. Uemoto T. Hata L. B. Gardner F. Chen A.-M. T. Baine Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University Graduate School of Medicine, 54 Shogoinkawara-cho, Sakyo-ku, Kyoto 606-8507, Japan e-mail: horit@kuhp.kyoto-u.ac.jp