CATALYTIC ANTIOXIDANTS IN ACUTE LUNG INJURY

本项目将专注于使用小分子量SOD模拟物来帮助理解活性氧及其在急性成人呼吸窘迫综合征（ARDS）模型中细胞室中的作用。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。这得到了急性呼吸窘迫综合征（ARDS）小动物和亚人类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，抗炎因子和促炎因子之间的平衡倾向于炎症，其特征是ROS/RNS在细胞外和细胞内空间的积累。该项目的目的是通过使用抗氧化剂（金属卟啉和金属四吡啶）抑制ROS/RNS的形成来调节ARDS急性肺损伤模型的早期炎症事件。这些研究有助于识别急性肺损伤期间ROS/RNS产生的细胞区室（细胞外和/或细胞内），并确定金属四吡咯（胆红素和胆绿素）是否在肺损伤中发挥内源性广谱抗氧化剂的作用。具体目的是：1)确定金属卟啉SOD模拟物是否调节狒狒急性肺损伤模型中的氧化应激；2)开发并表征了一类新的SOD模拟物——金属化四吡咯；3)确定新型SOD模拟物（金属化四吡咯）是否能调节急性肺损伤鼠模型的氧化应激；4)确定内源性金属四吡咯（胆红素和胆绿素的金属配合物）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.