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

一氧化碳（CO）是血红素催化的内源性副产物，已被证明在小鼠模型的各种器官中提供针对缺血再灌注损伤（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，我们在MHC近交系CLAWN小型猪中检测了（1）围手术期CO吸入对供体和受体肺移植物存活的影响（2）供体单独治疗是否足以延长移植物存活，以及（2）术后CO治疗是否具有额外的存活益处。（第0-11天; 35-45 ng/ml）。在第1组（n=6），接受者接受他克莫司单独。在第2组（n=5）中，供体和受体均吸入200-250 ppm CO（供体吸入180 min;受体吸入390 min，直至2 h再灌注）。在第3组（n=4）中，仅供体 关于我们 第4组（n=3），术后14天每天给予250 ppm CO，每天1小时，第1组所有受者术后63天均出现排斥反应，并产生细胞毒性抗供体抗体。相比之下，第2组中的5名受体中有4名接受了超过63天的移植物。短期CO治疗仅与供体（组3）是有效的，在延长移植物存活。4例受体中有3例接受移植物超过63天，最长存活时间为150天。在第4组中，2/3的受体维持移植物91天;然而，与第2组相比，术后CO并没有延长移植物存活。在接受CO治疗的动物中，通过MLR和CML测定的抗供体抗体和供体特异性反应性的发展被延迟。此外，第2- 4组的POD 2活检可见较少的炎性细胞浸润和内皮细胞损伤，血清促炎细胞因子（IL-1β、IL-6）浓度也降低。这些数据表明，在临床相关的大型动物模型中，供体CO单独治疗足以改善肺移植物的存活率。供体细胞保护预处理与CO在器官收获或保存可以在临床环境中完成，潜在地提高移植物的存活率，对受体的不良反应的风险很小。少

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