Vein wall remodeling after DVT is matrix metalloproteinase dependent

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This application's broad, long term objectives are to better define the mechanisms of post deep vein thrombosis (DVT) vein wall remodeling with an eye towards modifying the damage that occurs, and allow translation to human therapy. Post phelbitic syndrome occurs after DVT in a significant number of patients and results in leg pain, swelling, and occasionally ulceration. The costs to society are great in terms of lost productivity, and need for repeated health care visits. While efficacious therapy exists to prevent DVT propagation, none exist that directly modify vein wall damage. The basic mechanisms of vein wall remodeling after DVT include inflammatory cell influx, profibrotic growth factor production, collagen and elastin turnover, and matrixmetalloproteinases (MMP) activation. Specifically, preliminary data strongly suggests that the vein wall responds differently depending on the nature and duration of thrombus contact and is associated with increased MMP-2 and -9 activity. Whether these proteinases are responsible for the early damage and later fibrosis is not known, nor is it possible to predict which patients may develop post- phelbitic syndrome. Currenly available ultrasonographic and peripheral leukocyte genetic expression of MMPs in the setting of acute and chronic DVT is an unstudied area. THE OVERALL HYPOTHESIS IS THAT STASIS THROMBOSIS CAUSES VEIN WALL DAMAGE BY MMP ACTIVATION, LEADING TO LATE FIBROTIC INJURY. The current study will evaluate this hypothesis utilizing in vivo rodent models of DVT and a series of human patients with DVT by the following Specific Aims: I. To investigate in rat model of DVT: A) The mechanism by which thrombotic conditions regulate vein wall MMP-2, -9 expression; and B) To determine if exogenous MMP inhibitors can attenuate early vein wall injury; II. To demonstrate that down-regulation of MMP-2 and -9 activity inhibits late vein wall fibrotic injury after stasis DVT in a mouse model; III. To define ongoing vein wall injury in humans following DVT by duplex ultrasonography, and peripheral leukocyte gene and serum protein MMP-2 and -9 expression. This proposal will provide important mechanistic insight into the pathophysiology of post-phelbitic syndrome with real potential translation to decreasing the morbidity from this under-acknowledged disease.