In the original proposal, we were able to describe the effects of endotoxemia on lung mechanics in the unanesthetized sheep (an animal model of the adult respiratory distress syndrome--ARDS). We defined two possibly interrelated mechanisms that may be responsible, at least in part, for the alterations in lung mechanics observed following endotoxemia--cyclooxygenase products of arachidonate metabolism and inflammatory cells (especially granulocytes). We also demonstrated that endotoxemia acutely increased pulmonary responsiveness to aerosol histamine while granulocyte depletion decreased pulmonary responsiveness to aerosol histamine. These results generated a new hypothesis central to this competing renewal. We hypothesize that pulmonary inflammation mediates the alterations in lung mechanics associated with two interrelated clinical problems--ARDS and altered airway responsiveness as is observed in asthma. In this proposal, we expand our models of lung injury associated with pulmonary inflammation to two new models other than endotoxemia--phorbol myristate acetate (PMA) and zymosan activated plasma (ZAP) infusions. We propose to address our specific goals and hypotheses through the use of new techniques which allow us to more accurately measure changes in lung mechanics, pulmonary hemodynamics and lung fluid and solute exchange (including retrograde airway catheters and epithelial permeability, improved analytic methods and quantitative morphometrics). We will continue to try to elucidate important mechanisms responsible for the pathologic changes associated with endotoxemia, PMA, ZAP and altered airway responsiveness through assays of potential mediators, the use of specific blocking agents, granulocyte and platelet depletion and infusions and by studying the effects of infused potential mediators.
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