Recent studies have established a proinflammatory role of eosinophils in human diseases. However, the mechanisms of eosinophil recruitment and activation with release of granule proteins are only now being investigated. Four separate but related hypotheses will be tested in this proposal. First, we will test whether human eosinophil granule proteins and activated eosinophils themselves damage endothelial cells (EC). EC from several anatomical regions, including microvascular dermal EC, will be exposed to eosinophil granule proteins and to resting and activated eosinophils and their effects on viability, adhesion molecule expression, and morphology examined. Second, we will test whether eosinophils that have migrated through vascular constructs composed of microvascular EC overlaying extracellular matrix components become highly activated. Eosinophils which have migrated through the vascular constructs will be compared to control eosinophils for their ability to degranulate, to produce cytokines and leukotriene C4, and to express surface markers of activation, such as CD69. Third, we will test whether tissue eosinophilia in IL-5 transgenic mice is induced by exposure to IL- 4 and expression of the vascular cell adhesion molecule-1 (VCAM-1). Fourth, we will test whether tissue localization of eosinophils in human diseases is associated with expression of VCAM-1. These goals are integrated and designed to systematically evaluate interactions between vessels and eosinophils to explain their activities in human disease. Analyses of human biological fluids from patients with eosinophil- associated diseases will also be tested in these experiments to determine whether they are able to influence the interaction of EC and eosinophils. Finally, this project and Mechanisms of Activation of Human Eosinophils, Project 2, are closely linked.
| Plager, Douglas A; Davis, Mark D P; Andrews, Amy G et al. (2009) Eosinophil ribonucleases and their cutaneous lesion-forming activity. J Immunol 183:4013-20 |
