During the past project period, mechanisms of granulocyte- mediated tissue damage, particularly endothelial injury, have been investigated; work has included exploration of clinical contexts in which such damage occurs, dissection of mechanisms of granulocyte injury (using such tools as neutrophil cytoplasts), and a exploring granulocyte pharmacology and the interaction between granulocytes and other cell types. In the coming grant period, these basic themes will continue, but the emphasis will shift toward the study of mechanisms whereby granulocyte- mediated tissue injury may be enhanced. Special attention will be given to the following areas: First, the use of multiple sequential stimuli -- most prominently the use of """"""""priming"""""""" doses of such weak stimuli as platelet activating factor -- will be explored. PAF is a particularly interesting modulator, because it is capable of activating platelets as well as granulocytes and because it may be expressed upon the surface of endothelial cells when they are damaged. Second, some alterations of endothelial attractiveness to granulocytes and endothelial susceptibility to injury will be explored. Such study will include prior injury of endothelial cells, but most importantly will include exploration of the importance of Herpes virus infection of endothelial cells. We have preliminarily demonstrated that Herpes virus-infected endothelial cells are more susceptible to granulocyte-mediated injury; we shall continue to probe the role of Herpes simplex virus-induced neo-receptors for C3b and the Fc portion of immunoglobulin in the attraction of and adherence of granulocytes. Third, we shall look at another modulator of endothelial function, vasopressin, which as a mediator in shock is particularly attractive as a potential modifier of granulocyte-mediated endothelial injury in shock. Finally, we expect to take some of our earlier observations and some of the observations in the studies proposed at this time into lung explant and animal models. To this end, we have developed an explanted lung model of immune tissue injury which we expect to be particularly useful; we shall also continue to use a rabbit skin edema model, as in previous years.
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