The hypothesis to be examined in this proposal is that chronic venous insufficiency is the result of damage to the vein caused by an inflammatory response induced in the vein wall by thrombosis. The overall goal is a better understanding of the cellular and molecular mechanisms of inflammation that occur in the vein wall as a consequence of venous thrombosis. Using a model of IVC thrombosis in the rat, the study will: (1) characterize the temporal sequence and subpopulations of leukocytes that extravasate into the vein wall as consequence of venous thrombosis; (2) assess the etiologic role of leukocyte sequestration in the vein wall in the inflammatory response to thrombosis by passive immunization of experimental animals with specific monoclonal antibodies to various adhesion molecules (P-selectin, CD18, and ICAM-1); (3) characterize the temporal expression of several cytokines or chemokines in the vein wall in response to venous thrombosis; (4) assess the etiologic role of TNFa in the inflammatory response to thrombosis by passive immunization with a polyclonal antibody to TNFa; and (5) assess the etiologic role of various chemokines in the inflammatory response to thrombosis by passive immunization with appropriate specific, neutralizing antibodies. The proposal will employ a wide variety of immunologic, morphometric, and molecular biologic techniques to achieve these goals.
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