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

一氧化碳(CO)是血红素催化的一种内源性副产物，已被证明在小鼠模型中对多种器官的缺血再灌注损伤(IRI)具有保护作用。由于CO也是一种已知的有毒气体，在将其用于临床之前，使用大型动物进行转化研究是必不可少的。为了尝试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是否延长了移植肺的存活；(2)仅供体治疗就足以延长移植肺的存活；(2)术后CO治疗对MHC近交系CLAWN小型猪有额外的存活好处。18只CLAWN猪接受了完全MHC不匹配的肺，并使用了12天的他克莫司(0-11天；35-45 ng/ml)。第1组(n=6)，仅接受他克莫司治疗。在第2组(n=5)中，供者和受者均吸入200-250ppm的CO(供者为180min；受者为390min，直到再灌注2小时)。在第3组(n=4)中，只有供者为…CO治疗180min者。在第4组(n=3)，受者每天补充1小时250ppm的CO，持续14天。在术后第63天，所有受者一致排斥移植物，并产生细胞毒性抗供体抗体。相比之下，第二组5名受者中有4名接受了超过63天的移植。仅与供体进行短期CO治疗(第3组)能有效延长同种异体移植物的存活时间。4名受者中有3名接受了超过63天的移植，存活时间最长的为150天。在第4组中，2/3的受者移植物维持了91天；然而，与第2组相比，术后CO并没有延长移植物的存活时间。在接受CO治疗的动物中，通过MLR和CML检测的抗供体抗体和供体特异性反应性的发展被延迟。此外，2-4组肺组织炎性细胞浸润和内皮细胞损伤较少，血清促炎细胞因子(IL-1β，IL-6)浓度也降低。这些数据表明，在临床相关的大动物模型中，仅供体CO治疗就足以提高同种异体肺移植的存活率。在器官采集或保存期间用CO进行供体细胞保护性预适应可以在临床环境中完成，潜在地提高了移植物的存活率，而对受体的不良影响风险很小。较少

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