Our hypothesis is that alterations in blood oxidant-antioxidant balance contribute to endothelial cell (EC) and acute edematous lung injury (ARDS). We propose that release of toxic 02 metabolites (02*) from neutrophils primed byu endotoxin and stimulated by complement fragments or 02* derived serum factors and circulating or EC xanthine oxidase (XO) cause lung and kidney EC injury in part by oxidizing antiproteases which enhance neutrophil elastase toxicity. These reactions also increase and release 02* scavengers from RBC or damaged cells and initiate cytokine dependent increases in EC defenses. Our SCOR project includes 6 projects and 3 supporting cores which involve coordinated studies using in vitro, EC culture, isolated organ and intact animal systems which closely parallel ARDS patient studies. (Project One) Repine - XO derived 02 metabolites and elastase cause direct and neutrophil mediated injury to lung EC and isolated lungs. (Project Two) Worthen - Endotoxin and complement fragments promote neutrophil adherence to EC and retention in lung. (Project Three) White - Low dose cytokines )TNF/C-IL-1) project lung EC from neutrophil and 02 metabolite dependent injury. (Project Four) Linas - Complement activation, endotoxin and XO activity lead to neutrophil dependent 02* and elastase mediated renal injury. (Project Five) Harken - Thermal injury induced XO and complement activation, RBC lysis, and 02* and elastase mediated lung injury. (Project Six) Parsons - Changes in complement fragments, endotoxin. XO, and neutrophil and/or other activities may underlie and mediate ARDS. Special aspects deserve mention. First, emphasis is placed on blood (vs lavage) measurements to not only define mechanisms but also provide a practical way for selecting and monitoring ARDS patients. Second, kidney is included to elucidate potential systemic processes. Third, costs have been minimized by using a single city hospital, additional support and organization. This integrated effort will significantly improve understanding, diagnosis and treatment of ARDS.
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