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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) 是血红素催化的内源性副产品，已被证明可以在小鼠模型的多种器官中提供针对缺血再灌注损伤 (IRI) 的保护。由于二氧化碳也被认为是一种有毒气体，因此在临床使用之前，使用大型动物进行转化研究至关重要。为了尝试将 CO 应用于临床环境，我们检查了 (1) 供体和受体围手术期吸入 CO 是否可以延长肺移植物的存活时间 (2) 单独供体治疗足以延长移植物的存活时间 (2) 术后 CO 治疗对 MHC 近交 CLAWN 小型猪具有额外的存活益处。 18 只 CLAWN 猪在 12 天的时间里接受了完全 MHC 不匹配的肺。他克莫司（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，供体和受体均吸入 200-250 ppm CO（供体 180 分钟；受体 390 分钟，直到 2 小时再灌注）。在第 3 组 (n=4) 中，只有捐赠者接受了 CO 处理 180 分钟。在第 4 组 (n=3) 中，术后 14 天，受者每天额外接受 1 小时 250 ppm CO。第 1 组中的所有受者在术后第 63 天一致排斥移植物，并出现细胞毒性抗供体抗体。相比之下，第二组中五分之四的接受者在 63 天后接受了移植物。仅对供体（第 3 组）进行短期 CO 治疗可有效延长同种异体移植物的存活率。四分之三的接受者在超过 63 天后接受了移植物，最长的存活者持续了 150 天。在第 4 组中，三分之二的受者将移植物维持了 91 天；然而，与第 2 组相比，术后 CO 并没有延长移植物存活时间。接受 CO 治疗的动物中，MLR 和 CML 检测的抗供体抗体和供体特异性反应的产生延迟。此外，POD2 活检中发现炎症细胞浸润和内皮细胞损伤较少，并且 2-4 组中促炎细胞因子（IL-1β、IL-6）的血清浓度也有所下降。这些数据表明，仅供体 CO 治疗足以改善临床相关大型动物模型中肺同种异体移植物的存活率。在器官采集或保存过程中用CO对供体进行细胞保护性预处理可以在临床环境中完成，这可能会提高移植物的存活率，而对受体产生不良影响的风险很小。较少的