This application is for a new program that presents a multidisciplinary effort to investigate the Acute Respiratory Distress Syndrome (ARDS). The focus is on the initiation of lung damage secondary to systemic insults. The hypothesis is that generation of reactive oxygen species (ROS) by polymorphonuclear leukocytes (PMN) and endothelial cells results in acute oxidative injury to the pulmonary endothelium. This initiating injury incites subsequent amplification processes that evaluate in ARDS. This program will focus on novel mechanisms for initiation of ROS generation by PMN and endothelium, emphasizing the concept that these initiating mechanisms are ultimately responsible for lunge damage. The program consists of 4 research Projects and 5 supporting cores. Project 1 will investigate the role of PMN Fcgamma R1 receptors with the hypothesis that increased expression of these receptors and their interaction with immune complexes initiates ROS generation in ARDS. Project 2 proposes that ROS generation by pulmonary capillary endothelium in ARDS is mediated through ischemia-mediated activation of the endothelial cell NADPH oxidase complex. Project 3 will evaluate prognostic utility of several novel biomarkers of lung oxidative injury and their response to anti-oxidant therapy in patients with multiple trauma and/or severe sepsis. These biomarkers are serum protein carbonyls, serum protein nitrotyrosine, and urinary isoprostanes. Project 4 proposes a new approach to anti-oxidant therapy; it will evaluate mechanisms for site-directed antioxidant enzyme targeting, using antioxidant enzymes coupled therapy; it will evaluate mechanisms for site-direct antioxidant enzyme targeting, using antioxidant enzymes coupled to antibodies specific for endothelial cell membrane antigens. Thus, each of the 4 Projects proposes novel hypothesis that will evaluate: 1) mechanisms for initiation of cellular ROS each of the 4 Projects proposes novel hypothesis that will evaluate: 1) mechanisms for initiation of cellular ROS generation; 2) biomarkers for detection of increased ROS; and 3) therapy directed against increased ROS. Projects 1 and 3 will study patients while projects 1, 2 and 4 will use animal (rat, mice) models. The scientific Core are for patient registration, biostatistics and data management, analytical to assay for biomarkers of oxidative injury, and cell culture to provide cultures of various types of endothelial cells. The entire program will be supported by an administrative core. This coordinated program will provide new insights into the mechanisms for initiation of ROS-mediated acute lung injury, will evaluate potential biomarkers for its early detection, and will provide the mechanistic basis for new approaches to specific therapy.
Showing the most recent 10 out of 61 publications
