Department of Surgery, Division of Liver and Pancreas Transplantation, Dumont-UCLA Transplant Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Am J Transplant. 2011 Nov;11(11):2499-507. doi: 10.1111/j.1600-6143.2011.03700.x. Epub 2011 Aug 30.
Sotraustaurin (STN), a small molecule, targeted protein kinase C (PKC) inhibitor that prevents T-lymphocyte activation via a calcineurin-independent pathway, is currently being tested in Phase II renal and liver transplantation clinical trials. We have documented the key role of activated T cells in the inflammation cascade leading to liver ischemia/reperfusion injury (IRI). This study explores putative cytoprotective functions of STN in a clinically relevant rat model of hepatic cold ischemia followed by orthotopic liver transplantation (OLT). Livers from Sprague-Dawley rats were stored for 30 h at 4°C in UW solution, and then transplanted to syngeneic recipients. STN treatment of liver donors/recipients or recipients only prolonged OLT survival to >90% (vs. 40% in controls), decreased hepatocellular damage and improved histological features of IRI. STN treatment decreased activation of T cells, and diminished macrophage/neutrophil accumulation in OLTs. These beneficial effects were accompanied by diminished apoptosis, NF-κB/ERK signaling, depressed proapoptotic cleaved caspase-3, yet upregulated antiapoptotic Bcl-2/Bcl-xl and hepatic cell proliferation. In vitro, STN decreased PKCθ/IκBα activation and IL-2/IFN-γ production in ConA-stimulated spleen T cells, and diminished TNF-α/IL-1β in macrophage-T cell cocultures. This study documents positive effects of STN on liver IRI in OLT rat model that may translate as an additional benefit of STN in clinical liver transplantation.
索他洛尔（STN）是一种小分子，靶向蛋白激酶 C（PKC）抑制剂，可通过非钙调神经磷酸酶途径阻止 T 淋巴细胞活化，目前正在进行肾和肝移植的 II 期临床试验。我们已经证明了活化的 T 细胞在导致肝缺血/再灌注损伤（IRI）的炎症级联反应中起关键作用。本研究探讨了 STN 在临床相关的大鼠肝冷缺血后继发原位肝移植（OLT）模型中潜在的细胞保护作用。Sprague-Dawley 大鼠的肝脏在 UW 溶液中于 4°C 下储存 30 小时，然后移植到同基因受体。供体/受体或受体仅用 STN 治疗即可将 OLT 存活时间延长至>90%（对照组为 40%），减少肝细胞损伤并改善 IRI 的组织学特征。STN 治疗减少了 T 细胞的激活，并减少了 OLT 中的巨噬细胞/中性粒细胞积聚。这些有益作用伴随着凋亡减少、NF-κB/ERK 信号传导、促凋亡裂解 caspase-3 降低，但抗凋亡 Bcl-2/Bcl-xl 和肝细胞增殖增加。在体外，STN 减少了 ConA 刺激的脾 T 细胞中 PKCθ/IκBα 的激活和 IL-2/IFN-γ 的产生，并减少了巨噬细胞-T 细胞共培养物中的 TNF-α/IL-1β。本研究记录了 STN 在 OLT 大鼠模型中对肝 IRI 的积极影响，这可能转化为 STN 在临床肝移植中的额外益处。
