Targeted endothelial delivery of nanosized catalase immunoconjugates protects lung grafts donated after cardiac death.
Targeted endothelial delivery of nanosized catalase immunoconjugates protects lung grafts donated after cardiac death.
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DOI：
10.1097/tp.0b013e318226bc6b
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发表时间：
2011-08-27
期刊：
影响因子：
6.2
通讯作者：
Wiewrodt R
中科院分区：
文献类型：
--
作者：
Preissler G;Loehe F;Huff IV;Ebersberger U;Shuvaev VV;Bittmann I;Hermanns I;Kirkpatrick JC;Fischer K;Eichhorn ME;Winter H;Jauch KW;Albelda SM;Muzykantov VR;Wiewrodt R
供体器官短缺是肺移植的一个主要问题。心脏死亡后的捐赠有助于扩大器官池，但心脏骤停后的额外热缺血期加重了原发性移植物功能障碍。移植物的肺内皮是缺血再灌注过程中活性氧产生的重要来源和靶点。抗氧化酶过氧化氢酶结合血小板/内皮细胞粘附分子-1 （PECAM-1）抗体对纳米颗粒（抗pecam /过氧化氢酶偶联物）靶向保护移植物肺内皮细胞，可能改善心脏死亡和延长低温保存后供体肺移植的预后。18头猪进行左肺移植。在心脏骤停前，供体接受抗pecam /过氧化氢酶、非共轭组分混合物或载体溶液。在90分钟的热缺血和18小时的低温缺血后，移植肺，再灌注后6小时评估功能。取支气管肺泡灌洗液及肺组织标本。6只假手术的动物作为对照。在6小时再灌注期间，抗pecam /过氧化氢酶显著改善移植物功能，主要表现为气体交换的改善和肺内分流分数的降低。此外，脂质过氧化、肺泡渗漏和水肿形成在受保护的移植物中减少。移植后也出现类似的中度肺病理。抗pecam /过氧化氢酶纳米颗粒增强移植物肺内皮细胞的抗氧化能力，是心脏死亡后安全移植长期保存捐赠肺的直接途径。抗pecam /过氧化氢酶保护减轻了氧化应激，并允许立即重建正常的气体交换和肺微循环，这是改善移植物和患者预后的先决条件。
Donor organ shortage represents a major problem in lung transplantation. Donation after cardiac death could help to expand the pool of organs, but the additional period of warm ischemia after cardiac arrest aggravates primary graft dysfunction. The pulmonary endothelium of the graft constitutes an important source and target of reactive oxygen species generated during ischemia and reperfusion. Targeted protection of graft pulmonary endothelial cells by the antioxidant enzyme catalase, conjugated with a platelet/endothelial cell adhesion molecule-1 (PECAM-1) antibody to nanosized particles (anti-PECAM/catalase conjugates), might improve outcome in lung transplantation using donors after cardiac death and prolonged hypothermic preservation. Left lung transplantation was performed in 18 pigs. Before cardiac arrest, donors received anti-PECAM/ catalase, unconjugated component mixture or vehicle solution. After 90-min warm and 18-hr hypothermic ischemia, lungs were transplanted, and function was assessed during 6 hr after reperfusion. Samples of bronchoalveolar lavage fluid and lung tissue were taken thereafter. Six sham-operated animals served as controls. During 6-hr reperfusion, anti-PECAM/catalase significantly ameliorated graft function, evidenced by major improvements of gas exchange and reduced intrapulmonary shunt fraction. Furthermore, lipid peroxidation, alveolar leakage, and edema formation were reduced in protected grafts. Similarly moderate lung pathology was seen after transplantation. Augmentation of the antioxidant capacity of graft pulmonary endothelial cells with anti-PECAM/catalase nanoparticles represents a straightforward approach to enable a safe transplantation of prolonged preserved donation after cardiac death lungs. Anti-PECAM/catalase protection alleviated oxidative stress and allowed immediate reconstitution of normal gas exchange and pulmonary microcirculation, a prerequisite for improved graft and patient outcome.