281. Proton pump inhibitors suppress IL-1 mediated carditis in a murine model of Kawasaki disease

Background: Kawasaki disease (KD), is the leading cause of acquired heart disease in childhood, with a portion of children developing coronary artery lesions (CAL) despite standard of care treatment, intravenous immunoglobulin (IVIg). Murine and patient data indicate Interleukin-1 (IL-1) contributes to CALs. Calcium mobilization plays a role in inflammasome activation and is key to the immunobiology of KD. Proton pump inhibitors (PPI), a class of medications used to limit gastric acid secretion, have also been shown to have anti-inflammatory properties. Objective: To determine if PPIs inhibit IL-1 production and resulting CALs in the Lactobacillus casei cell wall extract (LCWE) induced coronary arteritis murine model of KD. Methods: Human monocyte cell line (THP1) derived macrophages and bone marrow derived macrophages (BMDMs) were stimulated with a TLR1/2 agonist Pam3Cys-Ser-(Lys)4 (Pam3Cys) and LCWE, in the presence or absence of PPIs. IL-1 was measured via ELISA. To exclude toxic effects, viability was tested via flow cytometry and trypan blue exclusion. Presence of caspase-1 was detected within BMDMs and murine heart tissue via Western Blot. Calcium flux was measured via fluorescent imaging plate reader on THP-1 macrophages. In vivo, KD was induced by intraperitoneal LCWE injection. Mice were injected with LCWE alone, LCWE+PPI, saline or PPI alone. Coronary artery inflammation was blindly scored by a pathologist. Results: Following stimulation with either Pam3Cys or LCWE, PPIs inhibited BMDM IL-1 production in a dose-dependent manner. Inflammasome activation is prevented by PPI inhibition of signal two. Stimulated macrophages treated with a PPI, in vitro, had a less calcium flux than untreated stimulated macrophages. In vivo, compared to untreated KD diseased mice, those treated with PPI were shown to have significantly reduced coronary artery inflammation based on overall cardiac severity score (p<0.01), area of inflammation (p<0.05) and elastin breakdown (p