Inflammatory reactions in the airways involve emigration of neutrophils across the blood vessel endothelium and then across the pulmonary epithelium. It is hypothesized that this inflammatory cell accumulation can lead to altered airway reactivity. Stimulated neutrophils can produce epithelial injury and/or increased permeability which may provide better access for antigens, mediators, and/or irritants to neuronal and/or humoral trigger mechanisms in the airway. In this project we will examine the mechanisms involved in four aspects of neutrophils emigration and epithelial injury: (1) adherence of neutrophils to the vascular endothelium, (2) transendothelial migration, (3) transepithelial migration, and (4) epithelial injury by neutrophils activated on the apical side of the epithelium. We will used cell culture techniques to study endothelial cells from large vessels and from the microvasculature and epithelial cells from alveoli and large airways. For many of the studies we will use human neutrophils and human endothelial and epithelial cells. Adherence will be assayed with radiolabeled neutrophils and with video microscopy with computer assisted image analysis. Migration will be studied in standard chemotactic chambers and in specially designed horizontal and vertical chambers for measurement of bioelectric properties of the monolayers and their permeability. Questions to be addressed include the following: Are there specific sites or macromolecules on endothelial cells or epithelial cells to which neutrophils attach? Do endothelial cells or epithelial cells produce factors which increase or decrease adherence? Do neutrophils alter the barrier properties of endothelial and epithelial monolayers during migration? Our central hypothesis is that endothelial cells and epithelial cells play an active role in neutrophil emigration,and once we know the mechanism for this facilitated movement, new pharmacologic strategies for control of inflammation may be possible. The mechanism of neutrophil adherence and migration should also be applicable to other inflammatory lung diseases such as pneumonia and adult respiratory distress syndrome.
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