Acute respiratory failure occurs commonly in patients who suffer severe burn injury. Furthermore, it is a major contributor to the death of these patients. The purpose of this project is to determine the effect of tumor necrosis factor-(TNF-) and burn-activated neutrophils on the endothelial cell actin cytoskeleton and to relate this to changes in pulmonary microvascular permeability. This project will also examine the role of oxygen-derived free radicals (ODFR) and endothelial cell gelsolin in mediating these cytoskeletal changes. There are four specific aims: 1) to determine the effect of TNF- and burn-activated neutrophils on pulmonary microvascular permeability; 2) to determine the effect of TNF- and burn-activated neutrophils on the endothelial cell actin cytoskeleton and to relate this to increases in microvascular permeability; 3) to determine the role of neutrophil-generated ODFR on the endothelial cell actin cytoskeleton and to relate this to increases in microvascular permeability; and 4) to determine the effect of TNF-and burn-activated neutrophils on endothelial cell gelsolin activity and to relate this to alterations in the actin cytoskeleton and microvascular permeability The research design involves the use of four complimentary experimental models: 1) in vivo rat model of burn injury in which the activity of TNF- alpha and neutrophil-endothelial cell adhesion are blocked; 2) in vitro perfused lung model in which neutrophils isolated from burned animals are infused into a normal rat lung perfused with TNF-alpha and various inhibitors of neutrophil-endothelial cell adhesion; 3) in vivo mouse model of burn injury utilizing animals with deletions of the genes for ICAM- 1/P-selectin and gelsolin; & 4) and endothelial cell monolayer exposed to TNF- and burn-activated neutrophils in the presence of various inhibitors of TNF- and ICAM-1. The principal endpoints include measures of microvascular permeability, endothelial cell actin cytoskeleton organization, and endothelial cell gelsolin activity. It is believed that by understanding how pro-inflammatory mediators, such as activated neutrophils and TNF-, alter the endothelial cell cytoskeleton new preventative or therapeutic strategies can be developed to limit the tremendous impact respiratory failure has on the outcome of patients suffering brain injury.
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