Beneficial Effects of Inhalation of Carbon Monoxide on Pulmonary Allograft Survival in MHC-inbred CLAWN Miniature Swine.

吸入一氧化碳对 MHC 近交 CLAWN 小型猪肺同种异体移植物存活的有益影响。

基本信息

批准号：
21791322
负责人：
SAHARA Hisashi
金额：
$ 2.75万
依托单位：
Kagoshima University (2010)Kyoto University (2009)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2010
项目状态：
已结题

项目摘要

Carbon monoxide (CO) is produced endogenously as a byproduct of heme catalysis, and has been shown to provide protection against ischemia-reperfusion injury (IRI) in a variety of organs in murine models. Since CO is also known to be a toxic gas, translational research using large animals is essential prior to its use in the clinic. To attempt CO to apply for the clinical setting, we examined whether (1) perioperative CO inhalation to both donor and recipient prolongs lung graft survival (2) donor treatment alone is sufficient to prolong graft survival and (2) postoperative CO therapy has additional survival benefits in MHC-inbred CLAWN miniature swine.Eighteen CLAWN swine received fully MHC mismatched lungs with 12 days of tacrolimus (days 0-11 ; 35-45 ng/ml). In Group 1 (n=6), recipients received tacrolimus alone. In Group 2 (n=5), both donors and recipients inhaled 200-250 ppm CO (180 min for donors ; 390 min for recipients until 2-hr reperfusion). In Group 3 (n=4), only donors were … More treated with CO for 180 min. In Group 4 (n=3), recipients were additionally given daily 1-hour 250 ppm CO for 14 postoperative days.All recipients in Group 1 uniformly rejected their grafts by postoperative day 63 with development of cytotoxic antidonor antibodies. In contrast, 4 out of 5 recipients in Group 2 accepted their grafts beyond 63 days. Short-term CO treatment only with donor (Group 3) was effective in prolonging allograft survival. Three out of 4 recipients accepted their grafts beyond 63 days with the longest survivor lasting 150 days. In Group 4, two out of 3 recipients maintained their grafts for 91 days ; however, postoperative CO did not prolong graft survival compared to Group 2. Development of antidonor-antibodies and donor-specific responsiveness by MLR and CML assays was delayed in animals that received CO therapy. Furthermore, fewer inflammatory cell infiltrates and injuries of endothelial cells were seen on POD2 biopsies, and serum concentrations of the pro-inflammatory cytokines (IL-1β, IL-6) also decreased in Group 2-4.These data suggest that donor CO treatment alone is sufficient to improve lung allograft survival in a clinically relevant large animal model. Donor cytoprotective preconditioning with CO during organ harvest or preservation could be accomplished in a clinical setting, potentially improving graft survival with little risk of adverse effects on the recipient. Less

一氧化碳（CO）作为血红素催化的副产品内源产生，并已证明可以在鼠模型中的各种器官中提供防止缺血 - 再灌注损伤（IRI）的保护。由于CO也是一种有毒气体，因此在诊所使用之前，使用大型动物进行翻译研究是必不可少的。 To attempt CO to apply for the clinical setting, we examined whether (1) periodic CO inhalation to both donor and recipient prolongs lung graft survival (2) donor treatment alone is sufficient to prolong graft survival and (2) postoperative CO therapy has additional survival benefits in MHC-inbred CLAWN miniature swine.Eighteen CLAWN swine received fully MHC mismatched lungs with 12 days of tacrolimus （第0-11天; 35-45 ng/ml）。在第1组（n = 6）中，接受者仅接受他克莫司。在第2组（n = 5）中，捐助者和接受者都吸入200-250 ppm CO（捐赠者为180分钟；接收者为390分钟，直到2小时再灌注）。在第3组（n = 4）中，只有捐助者是……用CO进行了180分钟的治疗。在第4组（n = 3）中，每天为14 ppm CO每天给予接受者14天。第1组中的所有接受者都通过术后第63天均匀地拒绝了其移植物，并通过细胞毒性抗体抗体的发展。对比，第2组的5名接收者中有4个接受了63天以上的移植物。仅用供体（第3组）治疗短期CO治疗可有效延长同种异体移植存活率。 4个接收者中有3个接受了63天以上的移植物，最长的幸存者持续150天。在第4组中，三分之二的接收者将其移植物保持91天。然而，与第2组相比，术后CO并未延长移植物的存活率。在接受CO治疗的动物中，MLR和CML分析的抗体抗体和供体特异性反应性延迟。此外，在POD2活检中，观察到较少的炎性细胞浸润和内皮细胞的损伤，在第2-4组中，促炎细胞因子（IL-1β，IL-6）的血清浓度也降低。这些数据表明，仅供体CO治疗足以改善临床相关的大型动物模型中的肺同种异体移植生存。在器官收获或保存过程中，可以在临床环境中完成对CO的供体细胞保护预处理，这可能会改善移植物存活率，而对接受者的不利影响风险很小。较少的