Harada Hirohisa, Wakabayashi Go, Takayanagi Atsushi, Shimazu Motohide, Matsumoto Kenji, Obara Hideaki, Shimizu Nobuyoshi, Kitajima Masaki
Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
Transplantation. 2002 Nov 27;74(10):1434-41. doi: 10.1097/00007890-200211270-00016.
The anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) is known to reduce hepatic ischemia-reperfusion injury. Therefore, we wished to examine the effect of IL-1Ra gene delivery into the rat liver on hepatic ischemia-reperfusion injury.
IL-1Ra cDNA was delivered into the rat liver by a single injection of the transgene vector into the portal vein using either the plasmid-cationic liposome or the recombinant adenoviral vector. At 24 hours after the gene delivery, rats were subjected to partial liver ischemia for 90 minutes followed by reperfusion. Liver tissue and serum samples were taken at 180 minutes of reperfusion, and the degree of the liver injury as well as the expression level of pro-inflammatory cytokines in the serum and tissue were investigated. In addition, we assessed the effect of IL-1Ra gene delivery on the 7-day survival rate when the nonischemic liver lobe was partially excised immediately following reperfusion.
In both cases of delivery methods, gene transfer of IL-1Ra resulted in significant elevation of serum IL-1Ra concentration, which reached maximal levels at 24 hours following the delivery. However, the highest serum concentration with the adenoviral vector was 1,000-fold of that in the liposome-treated animals. In the IL-1Ra delivered rats, liver damage, as well as production of pro-inflammatory cytokines, at 180 minutes of reperfusion was significantly reduced in a concentration-dependent manner of the circulating IL-1Ra protein. Rats subjected to the adenoviral vector gene delivery had higher 7-day survival rates compared with control animals.
IL-1Ra gene delivery into the liver may be of therapeutic use for abrogating hepatic ischemia-reperfusion injury after transplantation.
抗炎细胞因子白细胞介素-1受体拮抗剂（IL-1Ra）已知可减轻肝脏缺血再灌注损伤。因此，我们希望研究将IL-1Ra基因导入大鼠肝脏对肝脏缺血再灌注损伤的影响。
使用质粒-阳离子脂质体或重组腺病毒载体，通过向门静脉单次注射转基因载体将IL-1Ra cDNA导入大鼠肝脏。基因导入后24小时，对大鼠进行部分肝脏缺血90分钟，随后再灌注。在再灌注180分钟时采集肝脏组织和血清样本，研究肝脏损伤程度以及血清和组织中促炎细胞因子的表达水平。此外，我们评估了在再灌注后立即部分切除非缺血肝叶时，IL-1Ra基因导入对7天生存率的影响。
在两种递送方法中，IL-1Ra基因转移均导致血清IL-1Ra浓度显著升高，在递送后24小时达到最高水平。然而，腺病毒载体组的最高血清浓度是脂质体处理组动物的1000倍。在导入IL-1Ra的大鼠中，再灌注180分钟时的肝脏损伤以及促炎细胞因子的产生以循环IL-1Ra蛋白的浓度依赖性方式显著降低。与对照动物相比，接受腺病毒载体基因递送的大鼠7天生存率更高。
将IL-1Ra基因导入肝脏可能对减轻移植后肝脏缺血再灌注损伤具有治疗作用。
