When recirculating lymphocytes migrate from the microcirculation to the extravascular site of inflammation, they must overcome the mechanical forces produced by blood flow. Blood flowing across the vascular endothelium creates shear forces at the endothelial surface that are dependent on both flow velocity and vessel geometry. Because lymphocytic inflammation is associated with a 2-3 fold increase in blood flow, local shear forces should increase even further during inflammatory conditions. These shear forces disrupt the lymphocyte-endothelial cell adhesions necessary for transmigration. Based on preliminary work, the applicant has shown that lymphocyte slowing and transmigration in the inflammatory dermal circulation is associated with microangiectasias, i.e., focal structural dilatations of microvessel segments. These microvessels are inducible within 4 days of the onset of inflammation and lead to a greater than 10-fold local reduction in wall shear stress. The applicant has proposed a new microhemodynamic hypothesis of lymphocyte transmigration: that lymphocyte adhesion and transmigration occur in specialized vascular segments exhibiting structural changes that lead to decreased levels of flow velocity and wall shear stress. To investigate this hypothesis and study lymphocyte ruination through the inflammatory skin, the applicant has developed a sheep model that iPermits the long-term cannulation of both the blood and lymphatic circulations. In addition to quantifying migration by tissue morphometry, an epi-illumination intravital videomicroseopy system will be used to directly observe the migratory lymphocytes within microangiectasias. Further, the functional expression of endothelial and lymphocyte membrane molecules will be investigated with a panel of anti-sheep monoclonal antibodies. Using this model, the applicant proposes the following specific aims: 1) quantify the structural changes in vivo as well as connect structural data across a hierarchy of sizes (ranging from molecules to microangiectasias). 2) link the structural data to the kinetics of lymphocyte transmigration into inflammatory skin, 3) define the molecular mechanisms for selective lymphocyte transmigration within microangiectasias, and 4) develop a well-defined strategy for identifying soluble mediators capable of stimulating and inhibiting microangiectasia formation.
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