1490-P: Diabetes Induces Impaired Fibrotic Response to Mesh Involving Macrophage Dysfunction

Introduction: Women with diabetes have ~5-fold increased risk of mesh exposure into vaginal cavity following synthetic mesh augmentation in the surgical repair of pelvic floor disorders. To define the mechanism relevant to host fibrotic response, we studied the impact of diabetes on fibrillogenesis at mesh-tissue interface with a focus on the role of macrophages.

Methods: Diabetes was induced in Wistar rats using streptozotocin for 2 weeks. Rats w/wo diabetes underwent mesh implantation via sacrocolpopexy for 7- and 42-days (n=8 per time point per group). Fibrotic response (350μm adjacent to mesh), including thinner (G) vs. thicker (R) fibers and collagen density were quantified in Picrosirius Red images. TGF-β1 level in tissue extracts was measured using ELISA. Macrophage transcriptomics was sequenced following tissue dissociation and flow-sorting. CD68+αSMA+ cells were examined in tissue sections using immunofluorescence. CLC Genomics Workbench 22 (fold change>2, FDR<.05) and Mann-Whitney tests (p<.05) were used for statistics.

Results: In nondiabetics, the fibrotic response progressed with an increase in collagen density (p=0.008), and a decrease in TGF-β1 (p=.007) over time. The R/G ratio was not changed (p=.45). In contrast, diabetics displayed a deregulated pattern with impaired formation of thicker R fibers (p=.009), resulting in increased G fibers (p=.007) and decreased R/G (p=.014) at 42- vs. 7- days, while the collagen density and TGF-β1 level were unchanged over time (p=.49, .75). Paradoxically, macrophage expression of αSMA (myofibroblast marker) and major collagens (I, III, VI and VI) was increased ~4-fold relative to those in the nondiabetics at 42 days (FDR<.05). Cells with positively co-labeled CD68 (macrophage marker) and αSMA were identified at mesh-tissue interface.

Conclusions: Long-term diabetes negatively impacts host fibrotic response to mesh. The increase of macrophage-myofibroblast trandifferentiation in the process is yet to be elucidated.