Pravastatin Decreases Ileal Inflammation in a Murine Model of Ileitis

Abstract

Purpose: In addition to their lipid lowering properties, HMG CoA reductase inhibitors (statins) have been reported to have immunomodulatory properties primarily mediated by the inhibition of Th1 cytokines. Statins have been proposed as a potential therapy for a number of Th1-mediated chronic inflammatory diseases. Statins would be an intriguing therapy for Crohn's disease given their overall safety and tolerability. The aim of this study was to evaluate the effects of pravastatin on the severity of disease in a murine model of ileitis that closely resembles Crohn's disease (SAMP1/YitFc strain). Methods: We performed both a prevention and a treatment study using SAMP mice. In the prevention study, 4-week old mice received either pravastatin (10mg/kg, N = 6) or placebo (N = 6) as daily intraperitoneal injections for 6 weeks. In the treatment study, 12-week old mice with established ileitis received either pravastatin (10mg/kg, N = 6) or placebo (N = 6) as daily intraperitoneal injections for 2 weeks. Mice were sacrificed at the end of the study and ileal histology was graded on acute, chronic, and total inflammation by a blinded pathologist. Results: In the prevention study, mice receiving pravastatin had significantly lower acute (2.75 v. 4.2; p < 0.02), chronic (2.75 v. 4.2; p < 0.02), and total (5.5 v. 8.4; p < 0.02) ileal inflammatory scores compared to mice receiving placebo. In mice with established ileal disease, the group receiving pravastatin had significantly lower chronic ileal inflammation (1.17 v. 4.17; p < 0.002) but no significant differences in acute (4.42 v. 4.5; p= 0.94) or total (5.59 v. 8.67; p= 0.10) inflammatory scores than mice receiving placebo. Conclusions: Pravastatin prevents both acute and chronic inflammation, and significantly reduces chronic inflammation in SAMP1/YitFc mice. Since chronic inflammation in this model is mediated by Th1 cytokines, our results are consistent with the possibility that pravastatin suppresses Th1 cytokine production during chronic intestinal inflammation. Given the overall safety and tolerability of statins, the results of our preclinical study provides the proof of concept for testing statins in clinical trials with patients with Crohn's disease.