Development of the artificial liver assist device with normothermic xenoperfusion system of the whole liver

常温全肝异种灌注系统人工肝辅助装置的研制

• 批准号: 07507003
• 负责人: YAMAOKA Yosio
• 金额: $ 23.17万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07507003/
• 关键词: Liver Fallure; Liver Xenoperfusion; Liver Assist Device; Humoral Injury; Prostaglandin E1; Soluble Complement Receptor Type 1 (sCR1); プロスタグランジンE1; 人工肝補助装置; 体外肝灌流; 超急性拒絶反応; 1型可溶性補体受容体; 異種血液灌流; 常温持続灌流; 可溶性補体受容体

To assist various functions of the liver, usage of the xenogeneic pig liver as a liver assist device were evaluated in this progect. In this study, our original liver perfusion system, including continuous prostaglandin E1 administration, short cold ischemic time, physiological conditioning, enabled the pig liver to be xenoperfused more than 9 hours with adequate hepatic metabolic capacity. With this system, we succeeded in effective liver assist of the surgically induced liver failure dogs. These results were presented at both congresses of the American Society of the Artificial Internal Organ and American Society of Transplantation Physician in 1997. However, long-term pig liver xenoperfusion causes severe humoral injury via activation of human complement system by human anti-porcine xenoantigen. Hence, we had to conquer this xenogeneic humoral injury to develop more potent liver assist device. In this study, we revealed that recombinant soluble Complement Receptor type I (sCR1) dramatically suppressed humoral injury during xenoperfusion of the pig liver with human whole blood. With sCR1, xenoperfusion of the pig whole liver could be continued more than 24 hours with high hepatic function. To introduce this system to the clinical field, we established the xenogeneic organ usage system in April 1997 in Kyoto University Hospital. Now, we are evaluating the safety of the pig liver xenoperfusion system with baboon instead of human as a preclinical study.

为了辅助肝脏的各种功能，本研究对异种猪肝作为肝脏辅助装置的应用进行了评价。在本研究中，我们原有的肝脏灌流系统，包括连续给予前列腺素E_1，短的冷缺血时间，生理调节，使猪的肝脏异种灌流超过9小时，并有足够的肝脏代谢能力。利用该系统，我们成功地对外科诱导的肝功能衰竭犬进行了有效的肝脏辅助治疗。这些结果在1997年的美国人工内脏学会和美国移植内科学会的两次大会上公布。然而，长期的猪肝异种灌流通过人抗猪异种抗原激活人补体系统而导致严重的体液损伤。因此，我们必须克服这种异种体液损伤，以开发更有效的肝脏辅助装置。在这项研究中，我们发现重组可溶性补体受体I型(SCR1)显著抑制了猪肝脏与人全血异种灌流过程中的体液损伤。使用sCR1，猪全肝异种灌流可持续24小时以上，肝功能良好。为了将该系统引入临床领域，我们于1997年4月在京都大学医院建立了异种器官使用系统。现在，作为一项临床前研究，我们正在评估以狒狒代替人类的猪肝脏异种灌流系统的安全性。

项目成果

T.Yagi: "Discordant effects of xenogeneic pig liver perfusion on function of sinusoidal endothelial cells and parenchymal cells." Transprantation Proceedings. 28 (3). 1402-1403 (1996)

T.Yagi：“异种猪肝灌注对肝窦内皮细胞和实质细胞功能的不一致影响。”

T.Yagi: "Extracorporeal xenoperfusion of the pig liver as a liver assist device : Effects of prostaglandin E,and soluble complement receptor type 1" Transplantation Proceedings. 30. 74-75 (1998)

T.Yagi：“猪肝体外异种灌注作为肝脏辅助装置：前列腺素 E 和 1 型可溶性补体受体的影响”移植论文集。

Hiroaki Terajima: "Successful long-term xenoperfusion of the pig liver : continuous administration of prostaglandin E1 and insulin." Transplantation. in press

Hiroaki Terajima：“成功的猪肝长期异种灌注：持续施用前列腺素 E1 和胰岛素。”

Y. Shirakawa: "Inhibitory effect of plasma FKBP12 on immunosuppressive activity of FK506." Transplantation. 60. 1582-1587 (1995)

Y. Shirakawa：“血浆 FKBP12 对 FK506 免疫抑制活性的抑制作用。”

T. Yagi: "Extracorporeal xenoperfusion of the pig liver as a liver assist device : Effects of prostaglandin E_1 and soluble complement receptor type 1" Transplantation Proceedings. 30. 74-75 (1998)

T. Yagi：“猪肝体外异种灌注作为肝脏辅助装置：前列腺素 E_1 和可溶性补体受体 1 型的影响”移植论文集。