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.
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