P040 Caspase-8 blockade attenuates NSAID-induced colitis and cell death via NLRP3 inflammasome and NF-κB activation

Abstract Background Non-steroidal anti-inflammatory drugs (NSAIDs) are believed to exacerbate symptoms and inflammation in patients with inflammatory bowel disease (IBD). Recent studies indicate the gut microbiota may play a role NSAID-promoted inflammation. However, mechanism(s) underpinning NSAID-induced not fully understood. In this study, using piroxicam-accelerated model of colitis (PAC) IL-10-/- mice, we examined regulating colitis. Methods To establish whether plays PAC, mice were treated streptomycin for 24hrs followed by feeding 100 ppm piroxicam their food 9 days. inhibitor injected intra-peritoneally caspase-8 (Z-IETD-FMK, 10mg/kg) every other day starting before piroxicam-feeding. Colon tissue was collected on 14 analysis cell death markers qRT-PCR, MesoScaleDiscovery (MSD)-assay, western blot, histology. Faecal samples at different time-points 16S rRNA gene sequencing. Results A significantly higher expression colonic reduced epithelial barrier proteins elongated crypts found PAC-mice, which independent microbiota. Piroxicam did cause major changes fecal diversity or composition 14. An activation members NLRP3 inflammasome family including caspase-1 IL-1b, Caspase-8, pro-apoptotic -cleaved caspase 3 PARP- associated piroxicam-induced Inhibition ameliorated NSAID-provoked apoptosis preventing mitochondrial damage, downregulating NF-κB as well reducing cleaved caspase-3 PARP levels. Histology revealed an improvement morphology shorter immune infiltration lamina propria. Conclusion Our data provides evidence how NSAIDs can promote intestinal activating caspase-8, NF-κB, resulting induction apoptosis. Targeting Caspase-8 could be potential treatment strategy NSAID-worsened