Abstract
BACKGROUND: Post thrombotic syndrome is a fibrotic disease related to inflammation resolution. There are no direct therapies that can ameliorate this disease. Monocyte/macrophages (Mo/MØ) are the primary leukocyte involved with later venous resolution, and likely direct vein wall responses and healing. Herein, we explored the vein wall response with Mo/MØ depletion by two methods.
METHODS: Using two mouse models of venous thrombosis (VT), complete stasis and a flow restricted model, Mo/MØ depletion was accomplished using CD11b-DTR mice administered diphtheria toxin, and clodronate micelle administration in wild type mice. Tissue assays for structural histology, immunohistochemistry and western blotting were performed.
RESULTS: Mo/MØ depletion resulted in significantly less vein wall fibrotic thickness, in the stasis model at day 14 in both the CD11b-DTR mice and those receiving clodronate micelles. No significant effect of Mo/MØ depletion was observed in the flow restricted VT model. The decrease in vein wall fibrosis was associated with fewer DDR2+ vein wall cells in the CD11b-DTR mice, but no difference in endothelial luminal coverage. Decreased cytokine and growth factor expression of IL-6, FSP-1, and VEGFa were associated with Mo/MØ depletion. Lastly, PMN depletion was associated with increased proinflammatory Mo/MØ, and a trend towards increased vein wall fibrosis as compared with controls.
CONCLUSION: Mo/MØ direct the post VT late fibrotic response, possibly by affecting fibroblasts and inflammatory cytokine expression. This effect was only found with the complete stasis model and is consistent with worsened PTS in humans with complete venous obstruction.