Blood flowing across microvascular endothelium creates shear forces that must be overcome for lymphocytes to transmigrate into perivascular inflammatory tissues. The applicants propose the hypothesis that these forces are overcome by focal structural adaptations in the inflammatory microcirculation. These inflammation-inducible structural changes in the microcirculation-here referred to as microangiectasis-provide a mechanism for the controlled, localized creation of hemodynamic conditions suitable for lymphocyte adhesion and transmigration. Since these conditions must exist wherever lymphocytic inflammation occurs, the applicants propose that comparable structural changes exist in the systemic and pulmonary inflammatory microcirculation. To test these predictions, the applicants propose a combination of structural and functionall studies of microangiectasias in the skin, lung, gut and liver microcirculation. Corrosion casting and 3-dimensional scanning electron microscopy will be used to visualize and quantify the structural morphology of microangiectasias in the inflammatory microcirculation. The functional endpoint of microangiectasias, the transmigration of lymphocytes into extravascular tissues, will be investigated by both tissue cytometry and intravital microscopy. The applicants' preliminary intravital microscopy observation suggest that the motion of lymphocytes in microangiectasias is irregular and disordered; thus, the flow, there may be a recirculating (vortex) flow region in the microangiectasia dominating the motion of migrating cells. To investigate these possibilities, the applicants propose to study the carrier fluid mechanics and the motion of lymphocytes in the microangiectasias using computational fluid dynamic modeling. Finally, the applicants' studies of """"""""normal"""""""" lymphocytic inflammation will be extended to a genetically engineered model of focal vascular dilatations. The Endoglin hyploinsufficiency mouse, a model of the human disease hereditary hemorrhagic telangiectasias, demonstrates focal vascular dilatations that appear to be the pathologic manifestation of microangiectasias. The discovery of focal structural adaptations that regulate tissue entry in lymphocytic inflammation has immediate relevance for many areas of vascular biology and adds a new dimension to our understanding of inflammation.
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