Inflammatory responses associated with ischemia/reperfusion injury (IRI) play a central role in alloimmunity and transplant outcomes. A key event driving these inflammatory responses is the burst of reactive oxygen species (ROS), with hydrogen peroxide (H2 O2 ) as the most abundant form that occurs as a result of surgical implantation of the donor organ. Here, we used a syngeneic rat renal transplant and IRI model to evaluate the therapeutic properties of APP-103, a polyoxalate-based copolymer molecule containing vanillyl alcohol (VA) that exhibits high sensitivity and specificity toward the production of H2 O2 . We show that APP-103 is safe, and that it effectively promotes kidney function following IRI and survival of renal transplants. APP-103 reduces tissue injury and IRI-associated inflammatory responses in models of both warm ischemia (kidney clamping) and prolonged cold ischemia (syngeneic renal transplant). Mechanistically, we demonstrate that APP-103 exerts protective effects by specifically targeting the production of ROS. Our data introduce APP-103 as a novel, nontoxic, and site-activating therapeutic approach that effectively ameliorates the consequences of IRI in solid organ transplantation.

中文翻译：

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新型聚合物产品 APP-103 靶向移植物内活性氧，可减轻缺血/再灌注损伤并促进肾移植的存活。

与缺血/再灌注损伤 (IRI) 相关的炎症反应在同种免疫和移植结果中起着核心作用。驱动这些炎症反应的一个关键事件是活性氧 (ROS) 的爆发，其中过氧化氢 (H2 O2) 是由于供体器官手术植入而出现的最丰富的形式。在这里，我们使用同源大鼠肾移植和 IRI 模型来评估 APP-103 的治疗特性，APP-103 是一种基于聚草酸酯的共聚物分子，含有香草醇 (VA)，对 H2 O2 的产生表现出高灵敏度和特异性。我们证明 APP-103 是安全的，它能有效促进 IRI 后的肾功能和肾移植的存活。APP-103 在热缺血（肾钳夹）和长期冷缺血（同源肾移植）模型中减少组织损伤和 IRI 相关炎症反应。从机制上讲，我们证明 APP-103 通过专门针对 ROS 的产生发挥保护作用。我们的数据将 APP-103 介绍为一种新型、无毒、位点激活的治疗方法，可有效改善实体器官移植中 IRI 的后果。