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Racheal Robbins, Suzette Peng, Chantal M Moratz, Mechanisms of Coagulation-Complement pathway interplay in ischemia/reperfusion induced tissue injury., The Journal of Immunology, Volume 196, Issue 1_Supplement, May 2016, Page 187.9, https://doi.org/10.4049/jimmunol.196.Supp.187.9
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Abstract
Impaired fibrinolysis in systemic lupus erythematosus (SLE) is a contributing factor in disease complications including hyper-coagulation, tissue ischemia/reperfusion (IR), and increased risk of thrombosis: including stroke and deep vein thrombosis. Aberrant complement activation has been identified as a major factor in tissue injury in SLE. Previous work in the laboratory focused on mechanisms of complement activation in IR induced tissue injury in B6.MRL/lpr mice, an autoimmune prone mouse strain with a propensity to develop lymphadenopathy, glomerulonephritis, and polyarthritis. This work identified a C3-independent mechanism of downstream complement C5a generation contributing to tissue injury. Evidence of interplay between the coagulation and complement pathways was identified. Current work elucidates the mechanism by which the two pathways interact. Using a superior mesenteric artery IR model, we utilized complement and specific extrinsic or intrinsic coagulation pathway inhibitors to evaluate and compare resulting tissue pathology, generation of secondary inflammatory mediators, extent of innate immune activation, and generation of breakdown products involved in regulating feedback regulatory loops after ischemic/reperfusion injury. Inhibition of the extrinsic pathway had a greater impact on downstream complement activation, tissue pathology, vascular integrity, and recruitment of innate immune components versus the inhibition of the extrinsic pathway. Understanding the mechanisms of interplay between the pathways in the autoimmune mouse has significant clinical implications – especially in autoimmune diseases in which inflammation and hypercoagulability are known manifestations.
