Xenotransplantation Surgery Section, Frontier Science Research Center, Kagoshima University, Kagoshima, Japan.
Transplantation. 2010 Dec 27;90(12):1336-43. doi: 10.1097/TP.0b013e3181ff8730.
We have recently reported that perioperative low-dose carbon monoxide (CO) inhalation decreases lung ischemia-reperfusion injury in miniature swine. The aims of this study were to establish a large animal model of pulmonary allograft rejection using polymerase chain reaction-typed major histocompatibility complex (MHC)-inbred CLAWN miniature swine and to examine the effects of CO on allograft survival.
Eleven CLAWN miniature swines received fully MHC-mismatched lungs followed by 12 days of tacrolimus (days 0-11; blood level 35-45 ng/mL). Six recipients received tacrolimus alone (control group). Five recipients were additionally treated with inhaled CO (180 min for donors until graft harvest; 390 min for recipients until 2 hr after reperfusion).
All recipients treated with tacrolimus alone uniformly rejected their grafts by postoperative day 63 with development of cytotoxic antidonor antibodies. CO treatment was effective in prolonging allograft survival from a mean of 47±7 to 82±13 days (P=0.017), with one CO-treated animal maintaining function until postoperative day 120. Development of antidonor antibodies and donor-specific responsiveness by cell-mediated lympholysis and mixed lymphocyte reaction assays was delayed in animals that received CO therapy. Furthermore, serum concentrations of proinflammatory cytokines (interleukin-1β and -6) 1 day after transplant were significantly decreased in the CO-treated group.
Fully MHC-mismatched lungs in CLAWN miniature swine were consistently rejected within 63 days, suggesting that this is a robust large animal model ideal for investigating mechanisms and treatment of lung rejection. Perioperative low-dose CO inhalation prolonged graft survival and inhibited antidonor antibody production and was associated with decreased proinflammatory mediators in this model.
我们最近报道了围手术期吸入低剂量一氧化碳（CO）可减轻小型猪肺缺血再灌注损伤。本研究的目的是建立一种使用聚合酶链反应（PCR）型主要组织相容性复合物（MHC）近交 CLAWN 小型猪的肺移植排斥的大动物模型，并研究 CO 对移植物存活的影响。
11 头 CLAWN 小型猪接受完全 MHC 错配的肺脏，然后接受 12 天的他克莫司（第 0-11 天；血药浓度 35-45ng/ml）治疗。6 名受体仅接受他克莫司（对照组）治疗。5 名受体还接受吸入 CO 治疗（供体在收获移植物前吸入 CO180 分钟；受体在再灌注后 2 小时内吸入 CO390 分钟）。
所有接受他克莫司单独治疗的受体在术后第 63 天均排斥其移植物，产生细胞毒性抗供体抗体。CO 治疗能有效延长移植物存活时间，从平均 47±7 天延长至 82±13 天（P=0.017），1 只 CO 治疗动物的移植物功能一直维持到术后第 120 天。CO 治疗组动物的抗供体抗体和细胞介导的淋巴溶解和混合淋巴细胞反应试验的供体特异性反应的发展被延迟。此外，CO 治疗组在移植后第 1 天血清中促炎细胞因子（白细胞介素-1β 和 -6）的浓度显著降低。
CLAWN 小型猪的完全 MHC 错配肺在 63 天内被一致排斥，这表明这是一种强大的大动物模型，非常适合研究肺排斥的机制和治疗方法。围手术期低剂量 CO 吸入可延长移植物存活时间，抑制抗供体抗体产生，并与该模型中促炎介质的减少有关。
