Division of Transplantation, Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Hepatology. 2011 Jun;53(6):2016-26. doi: 10.1002/hep.24317.
Hepatocyte proliferation early after liver resection is critical in restoring liver mass and preserving function as the liver regenerates. Carbon monoxide (CO) generated by heme oxygenase-1 (HO-1) strongly influences cellular proliferation and both HO-1 and CO are accepted hepatoprotective molecules. Mice lacking functional HO-1 were unable to mount an appropriate regenerative response following partial hepatectomy (PHTx) compared to wildtype controls. We therefore hypothesized that exogenous administration of CO at low, nontoxic concentrations would modulate hepatocyte (HC) proliferation and liver regeneration. Animals treated with a low concentration of CO 1 hour prior to 70% hepatectomy demonstrated enhanced expression of hepatocyte growth factor (HGF) in the liver compared to controls that correlated with a more rapid onset of HC proliferation as measured by phospho-histone3 staining, increased expression of cyclins D1 and E, phosphorylated retinoblastoma, and decreased expression of the mitotic inhibitor p21. PHTx also increased activation of the HGF receptor c-Met, which was detected more then 9 hours earlier in the livers of CO-treated mice. Blockade of c-Met resulted in abrogation of the CO effects on HC proliferation. Corresponding with increased HC proliferation, treatment with CO maintained liver function with normal prothrombin times versus a 2-fold prolongation in controls. In a lethal 85% PHTx, CO-treated mice showed a greater survival rate compared to controls. In vitro, CO increased HGF expression in hepatic stellate cells, but not HC, and when cocultured together led to increased HC proliferation. In summary, we demonstrate that administration of exogenous CO enhances rapid and early HC proliferation and, importantly, preserves function following PHTx. Taken together, CO may offer a viable therapeutic option to facilitate rapid recovery following PHTx.
肝切除术后早期肝细胞增殖对于肝脏再生过程中恢复肝脏质量和维持功能至关重要。血红素加氧酶-1（HO-1）产生的一氧化碳（CO）强烈影响细胞增殖，HO-1 和 CO 均被认为是具有肝保护作用的分子。与野生型对照相比，缺乏功能性 HO-1 的小鼠在部分肝切除（PHTx）后无法产生适当的再生反应。因此，我们假设外源性给予低浓度、无毒的 CO 会调节肝细胞（HC）增殖和肝脏再生。与对照组相比，在进行 70%肝切除前 1 小时用低浓度 CO 处理的动物，其肝脏中肝细胞生长因子（HGF）的表达增强，这与磷酸化组蛋白 3 染色所测量的 HC 增殖更快有关，cyclin D1 和 E、磷酸化视网膜母细胞瘤的表达增加，以及有丝分裂抑制剂 p21 的表达减少。PHTx 还增加了 HGF 受体 c-Met 的激活，CO 处理小鼠肝脏中 c-Met 的激活比对照组早 9 个多小时检测到。阻断 c-Met 导致 CO 对 HC 增殖的作用被阻断。与 HC 增殖增加相对应，CO 治疗维持了肝功能，凝血酶原时间正常，而对照组则延长了 2 倍。在致死性 85%PHTx 中，CO 处理的小鼠与对照组相比具有更高的存活率。在体外，CO 增加了肝星状细胞中的 HGF 表达，但不增加 HC，并且当共培养时，导致 HC 增殖增加。总之，我们证明外源性 CO 的给予增强了快速和早期的 HC 增殖，并且重要的是，在 PHTx 后维持了功能。总之，CO 可能提供一种可行的治疗选择，以促进 PHTx 后的快速恢复。
