Acute inflammation at a local site in the lung, in contrast tot he systemic circulation, is accompanied by a local decrease in blood flow (flow diversion) which limits the degree of neutrophil influx. Preliminary experiments suggest that the process is neutrophil-dependent and involves thromboxane and PAF; thus neutrophils may regulate their own accumulation through the generation of lipid mediators. This proposal seeks to determine the mechanisms of this effect, the means to modulate it, and its role in pulmonary inflammation. We will induce inflammation with C5a and immune complexes in intact rabbits in vivo, in the isolated perfused rabbit lung, and use both human and rabbit cells to test four hypotheses regarding the hemodynamic response to inflammation in the lung. Hypothesis 1. Neutrophils and endothelial cells are required to generate thromboxane, which initiates the vasoconstriction. The cell and mediator requirements for the decrease in blood flow will be studied (including the possible role of the sulfidopeptide leukotrienes) using depletion experiments and manipulation of the isolated lung perfusate. Hypothesis 2. Thromboxane production is the result of neutrophil stimulation of endothelial cells by PAF, and requires intimate contact between the two cell types. Immunocytochemical localization of thromboxane synthase and metabolic labelling and mass spectrometry of stable isotopes will be used to determine the cellular source of thromboxane, nature of PAF presentation, and intermediate transfer. Hypothesis 3. Persistence of the decrease in blood flow is due to capillary obstruction by neutrophils or neutrophil/platelet aggregates, and/or other mediators, such as the long-acting vasoconstrictor, endothelin. Hypothesis 4. The decrease in blood flow regulates the inflammatory response in the lung. This possibility will be tested by determining the effects of agents that modulate flow on vascular permeability, the scintigraphic accumulation of neutrophils labelled with 111-Indium, and other indices of the severity of the inflammatory response. These findings will be compared with those in the skin where inflammation is associated with local vasodilatation, mediated through vasodilator prostaglandins. These studies will further define the hemodynamic and cellular responses of inflammation in the lung, provide a better understanding of the mechanisms involved, and suggest new intervention strategies.
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