Bejaoui Mohamed, Pantazi Eirini, De Luca Viviana, Panisello Arnau, Folch-Puy Emma, Serafin Anna, Capasso Clemente, C T Supuran, Rosselló-Catafau Joan
Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.).
Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona-Spanish National Research Council, Barcelona, Catalonia, Spain (M.B., E.P., A.P., E. F.-P., J. R.-C.); Institute of Bioscience and Bioresources, National Research Council, Napoli, Italy (V.D.L., C.C.); University of Florence, Neurofarba Department, Sesto Fiorentino, Firenze, Italy (S.C.T.); and Platform of Laboratory Animal Applied Research, Barcelona Science Park, Barcelona, Catalonia, Spain (A.S.)
J Pharmacol Exp Ther. 2015 Nov;355(2):191-8. doi: 10.1124/jpet.115.225177. Epub 2015 Sep 1.
Ischemia reperfusion injury (IRI) is a primary concern in liver transplantation, especially when steatosis is present. Acetazolamide (AZ), a specific carbonic anhydrase (CA) inhibitor, has been suggested to protect against hypoxia. Here, we hypothesized that AZ administration could be efficient to protect fatty livers against cold IRI. Obese Zucker rat livers were preserved in Institut Georges Lopez-1 storage solution for 24 hours at 4°C and ex vivo perfused for 2 hours at 37°C. Alternatively, rats were also treated with intravenous injection of AZ (30 mg/kg) before liver recovery. Liver injury, hepatic function, and vascular resistance were determined. CA II protein levels and CA hydratase activity were assessed as well as other parameters involved in IRI (endothelial nitric oxide synthase, mitogen activated protein kinase family, hypoxic inducible factor 1 alpha, and erythropoietin). We demonstrated that AZ administration efficiently protects the steatotic liver against cold IRI. AZ protection was associated with better function, decreased vascular resistance, and activation of endothelial nitric oxide synthase. This was consistent with an effective mitogen activated protein kinase inactivation. Finally, no effect on the hypoxic inductible factor 1 alpha/erythropoietin pathway was observed. The present study demonstrated that AZ administration is a suitable pharmacological strategy for preserving fatty liver grafts against cold IRI.
缺血再灌注损伤（IRI）是肝移植中的一个主要问题，尤其是在存在脂肪变性的情况下。乙酰唑胺（AZ）是一种特异性碳酸酐酶（CA）抑制剂，已被认为可预防缺氧。在此，我们假设给予AZ可能有效地保护脂肪肝免受冷IRI损伤。将肥胖 Zucker 大鼠的肝脏在 Georges Lopez-1 保存液中于 4°C 保存 24 小时，并在 37°C 下进行 2 小时的离体灌注。另外，在肝脏回收前，大鼠也接受静脉注射 AZ（30mg/kg）治疗。测定肝损伤、肝功能和血管阻力。评估 CA II 蛋白水平和 CA 水合酶活性以及 IRI 中涉及的其他参数（内皮型一氧化氮合酶、丝裂原活化蛋白激酶家族、缺氧诱导因子 1α和促红细胞生成素）。我们证明给予 AZ 可有效保护脂肪变性肝脏免受冷 IRI 损伤。AZ 的保护作用与更好的功能、降低的血管阻力以及内皮型一氧化氮合酶的激活有关。这与有效的丝裂原活化蛋白激酶失活一致。最后，未观察到对缺氧诱导因子 1α/促红细胞生成素途径的影响。本研究表明，给予 AZ 是一种适合保护脂肪肝移植物免受冷 IRI 损伤的药理学策略。
