Post-thrombotic syndrome (PTS) is the most common sequelae from deep vein thrombosis (DVT), characterized by vein wall fibrosis, valve destruction and often occlusion. It is estimated to occur in ~40 ? 50% of those suffering a DVT. No direct medical therapy exists to treat PTS, highlighted by the recent failure of graded compression stockings to prevent PTS (SOX trial). The CaVenT trial suggested that even those patients treated with thrombolysis still have a ~40% incident PTS at 2 years. Recurrent DVT is a particularly strong factor increasing the risk of PTS, prevented in part by anticoagulation. However, bleeding risks remain even with the new non-vitamin-K antagonists. Interleukin-6 (IL-6) is a pleotropic inflammatory cytokine that is uniquely associated with both PTS and experimental vein wall injury. IL-6 has two primary signaling pathways. Direct IL-6 binding to membrane bound IL-6 receptor-alpha (R?) occurs in a limited number of cells, such as hepatocytes and leukocytes, and is termed `classical'. More commonly, IL-6 complexes with soluble IL-6R? and binds the co-receptor gp130, present on most cells, termed `trans-signaling', and confers most inflammatory and fibrotic sequelae. Preliminary and published data suggests strong correlation of IL-6 with vein wall fibrosis, co-localization with endothelial and vascular smooth muscle cells (VSMC), and altered fibrosis in IL-6-/- mice after venous thrombosis (VT). These observations suggest a central role for IL-6 signaling in post- thrombotic vein wall injury, and importantly, for which readily translatable anti-IL-6 therapies already exist. Our overall hypothesis is that IL-6/sIL-6R? trans-signaling drives downstream profibrotic vein wall cellular changes that cause experimental post-thrombotic vein wall injury and that novel anti-IL-6 signaling therapies can abrogate post-thrombotic vein wall injury. We will address this hypothesis by three specific aims:
Specific Aim 1 : To define the early sources and mechanisms of IL-6 and sIL-6R? release after VT, the early vein wall cellular responses, and the effect of thrombosis model.
Specific Aim 2 : To demonstrate the vein wall endothelial and VSMC specific profibrotic activities driven by IL-6/IL-6R?/gp130 signaling axis after VT.
Specific Aim 3 : To prevent and treat post-thrombotic vein wall injury using novel direct and indirect anti-IL-6 therapies, as a comparison with standard of care anticoagulation, in primary and recurrent experimental VT. To accomplish these Aims, murine models of stasis and stenosis derived VT, as well as ex vivo vein wall culture will be used. Tissue specific transgenic mice to define the mechanisms of IL-6 signaling on vein wall fibrotic injury, and novel non anticoagulant anti-IL-6 therapies will be tested. The proposed experiments herein will significantly move the field forward by defining the mechanisms of IL-6 signaling, and the translation of IL-6 inhibition on experimental PTS, using novel and clinically available agents.
The proposed research is relevant to the public health because the discovery of new knowledge of post thrombotic pathophysiology related to interleukin-6, and its application to novel treatment strategies without the dangers of anticoagulation, can reduce morbidity and mortality. The proposed research is relevant to the NIH mission in that new knowledge related to venous thrombosis and post thrombotic syndrome will be broadly disseminated, and lead to better therapies to reduce the burden of this common disease.
