OP38 Modulation of the septin cytoskeleton ameliorates intestinal fibrogenesis

Abstract Background Fibrosis-induced intestinal strictures leading to obstruction are a common and serious complication of Crohn’s disease (CD) with currently no available specific anti-fibrotic therapies. Cytoskeletal dynamics in mesenchymal cells associated organ fibrogenesis. Septin filaments novel cytoskeletal element, but the functional role septins regulating inflammation fibrosis remain unknown. We examined involvement septin cytoskeleton modulating fibrogenic signaling fibrogenesis vitro vivo. Methods Expression different human resection tissues, primary myofibroblasts (HIMF) immortalized colonic myofibroblast (CCD 18co cells) were by real-time PCR immunoblotting. Functional inhibition was achieved using siRNA for 7 cell-permeable small molecule forchlorfenuron (FCF). Migration proliferation HIMF wound healing thymidine incorporation assays, respectively. Levels secreted cytokines measured cytometric bead array. Roles development vivo studied chronic DSS colitis model mice administration FCF or vehicle. Results All genes expressed tissues predominant expression 7. Pro-fibrotic transforming growth factor-β1 (TGFβ1) triggered activation manifested increased production ECM proteins such as fibronectin collagen 1 enhanced markers α-smooth muscle actin, L-caldesmon tropomyosin. knockdown resulted loss other thereby disrupting entire cytoskeleton. Either pharmacological, genetic disruption reversed effect TGFβ1 attenuating reducing markers. Interestingly, these effects only found on protein level not due changes gene expression, suggesting their at post-transcriptional level. Moreover, pharmacological disruptions reduced migration, attenuated cytokine secretion activated myofibroblasts. did affect inflammation, decreased score during mice. Conclusion Our data highlights regulator function. This first time implicates an active participant potential target therapies IBD patients.