CATALYTIC ANTIOXIDANTS IN ACUTE LUNG INJURY

描述（改编自申请人的摘要）本项目将集中于使用小分子量SOD模拟物，以帮助了解活性氧及其在成人呼吸窘迫综合征（ARDS）急性模型细胞室中形成的作用。 活性氧（ROS）和活性氮（RNS）与氧和内毒素介导的急性肺损伤机制直接相关。 这得到了来自急性呼吸窘迫综合征（ARDS）的小动物和亚人灵长类动物模型的实验证据的支持。 统一的假设表明，在急性肺损伤中，抗炎和促炎元素之间的平衡倾向于炎症，其特征在于细胞外和细胞内空间中ROS/RNS的积累。本项目的目的是通过使用抗氧化剂（金属卟啉和金属化四吡咯）抑制ROS/RNS形成来调节ARDS急性肺损伤模型中的早期炎症事件。这些研究可以帮助确定细胞腔室（细胞外和/或细胞内），其中ROS/RNS在急性肺损伤过程中出现，并确定金属化四吡咯（胆红素和胆绿素）是否作为内源性广谱抗氧化剂在肺损伤中发挥作用。 具体目标是：1）确定金属卟啉SOD模拟物是否调节急性肺损伤的狒狒模型中的氧化应激; 2）开发和表征一类新的SOD模拟物，金属化四吡咯; 3）确定一类新的SOD模拟物是否（金属化四吡咯）调节急性肺损伤啮齿动物模型中的氧化应激;和4）确定内源性金属化四吡咯（胆红素和胆绿素的金属络合物）是否在血红素加氧酶的抗氧化作用中起重要作用。

Description (Adapted from Applicant's Abstract) This project will focus on the use of small molecular weight SOD mimetics to help understand the role of reactive oxygen species and their formation in cellular compartments in acute models of adult respiratory distress syndrome (ARDS). Reactive oxygen species (ROS) and reactive nitrogen species (RNS) have been directly linked to the mechanism of oxygen- and endotoxin- mediated acute lung injury. This is supported by experimental evidence from small animal and sub-human primate models of acute respiratory distress syndrome (ARDS). The unifying hypothesis suggests that in acute lung injury, the balance between anti-inflammatory and pro-inflammatory elements is tipped towards inflammation which is characterized by the accumulation of ROS/RNS in both extracellular and intracellular spaces. The objective of this project is to modulate early inflammatory events in acute lung injury models of ARDS by inhibiting ROS/RNS formation with the use of antioxidants (metalloporphyrin and metallated tetrapyrroles). These studies can help identify the cellular compartments (extracellular and/or intracellular) in which ROS/RNS arise during acute lung injury and determine if metallated tetrapyrroles (bilirubin and biliverdin) function as endogenous broad-spectrum antioxidants in lung injury. The Specific Aims are: 1) Determine if a metalloporphyrin SOD mimetic modulates oxidative stress in the baboon model of acute lung injury; 2) Develop and characterize a new class of SOD mimetics, metallated tetrapyrroles; 3) Determine if the new class of SOD mimetics (the metallated tetrapyrroles) modulate oxidative stress in rodent models of acute lung injury; and 4) Determine whether endogenous metallated tetrapyrroles (metal complexes of bilirubin and biliverdin) play an essential role in the antioxidant effects of heme oxygenase.