DYSREGULATED EXPRESSION OF SIGNALING MOLECULES IN ACUTE LUNG INJURY

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A fundamental hypothesis in our Special Center of Research is that dysregulated cell-cell interactions initiate and/or amplify inflammatory injury to the alveolar capillary membrane in Acute Respiratory Distress. Syndrome (ARDS), a common and lethal cause of lung damage, and that endothelial cells are critically involved. Identification of signaling molecules and other factors dysregulated cell-cell interactions in ARDS is a central and long-term goal of this project. In the current application, we focus on signaling molecules for neutrophils synthesized by stimulated and injured human endothelial cells. Neutrophils (PMNs) initiate, amplify, and influence the maintenance and outcome of acute lung injury. Endothelial cells are the first structural cells that PMNs encounter in the inflamed and injured lung and, by virtue of their ability to synthesize signaling molecules on a variety of classes, are particular points of dysregulated information transfer to the leukocytes. The mechanisms that regulate the expression and biologic actions of endothelial signaling molecules of the same or different classes, the identities of some of these signaling factors, and the mechanisms by which they become dysregulated in inflammatory injury are largely unknown. This project addresses each of these issues in interrelated studies based on the above hypotheses and on observations and preliminary data generated in the current funding period. The first specific aim is to characterize the regulation of expression and actions of chemokines produced by human endothelial cells that signal neutrophil activation, focusing on ENA-78 and related family members. The second specific aim is to characterize new endothelial signaling factors that we have identified by screening cDNA libraries from stimulated endothelial cells and by subtractive hybridization. The third specific aim is to characterize expression and distribution of endothelial signaling molecules in lung tissue from patients with ARDS and in tissue from control and comparative subjects. The fundamental and correlative nature of these studies will yield new knowledge that may lead to novel strategies of prevention and therapy of ARDS.