The priming of pulmonary vascular endothelial cells with cytokines (TNFalpha or IL-1alpha) may be a critical event in the mechanism of lung microvascular injury. We hypothesize that TNF and IL-1 mediated priming of pulmonary vascular endothelial cells promotes and enhances neutrophil (PMN)-dependent lung vascular injury. This effect of cytokines may require the expression of endothelial ligand ICAM-1 for PMN CD18 integrin and/or another endothelial adhesive molecule, ELAM, as well as enhanced activation of the PMN sequestered in the pulmonary vascular bed. Studies will be made in rabbit lungs using the isolated-perfused lung preparation, in intact rabbits, and rabbit pulmonary artery endothelial monolayers. The first series of studies will address the effects of cytokine treatment of lungs in potentiating PMN-mediated pulmonary vascular injury and edema. Studies will then examine the basis of the potentiation; that is, (i) role of pulmonary vascular PMN uptake following cytokine challenge of lungs and (ii) role of enhanced PMN activation responses in the mediation of lung vascular injury and lung tissue edema. Specifically, these studies will address the mechanisms of PMN uptake with respect to the role of PMN CD18 glycoprotein and the endothelial adhesion molecules, ICAM-1 and ELAM-1, and whether these endothelial adhesion proteins are involved in the enhancement of PMN activation responses. The final series of studies will examine whether an exaggerated release of arachidonic acid metabolites and PAF from PMN sequestered in cytokine-challenged lungs mediates the intensified pulmonary vasoconstriction. The increase in pulmonary capillary hydrostatic pressure resulting from increased pulmonary vasomotor tone may contribute to the development of pulmonary edema. The studies are aimed at defining better the mechanism of pathogenesis of adult respiratory distress syndrome (ARDS), which may involve release of TNFalpha and IL-1alpha after a period of endotoxemia. The results should provide novel insights into the mechanism of ARDS, and, particularly, into the role of endothelial adhesion molecules in the mediation of lung vascular injury, which will then, hopefully, allow the development of new therapeutic strategies to control lung injury.
NIH ExPorter
NIH ExPorter