Polymorphonuclear leukocytes (PMN) play a role in the development of high permeability edema (HPLE) in many animal models but the mechanisms by which PMN cause the edema are not all known. Using an in vitro model of the endothelium, I will examine the ability of nonoxidant, nonproteolytic neutrophil-derived cationic proteins to mediate edema formation. Previous work has shown that cationic agents are able to increase vascular permeability in many different capillary beds. In preliminary studies it was found that neutrophil cationic proteins, inactive neutrophil elastase and the polycation protamine can increase albumin transfer across an endothelium. Protamine also increased the hydraulic conductivity (LP) of the endothelium. The proposed study will focus on determining the mechanism of action of these cationic proteins. Initial studies will focus on confirming the ability of these agents to increase albumin permeability and the hydraulic conductivity of the endothelium. The importance of the cationic charge of these molecules in their effects on endothelial integrity will also be evaluated. Later studies will focus on how these cationic molecules alter the endothelium including the effect of neutralizing the negative luminal surface charge on endothelium, the direct toxicity of these cationic proteins to endothelial cells, the action of the cationic proteins on the lipid membrane of endothelial cells, and the ability of the cationic proteins to unmask surface receptors on the endothelial cells.
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