Corticotropin-releasing hormone antagonists possess anti-inflammatory effects in the mouse ileum

Abstract

Background & Aims: Corticotropin-releasing hormone (CRH) released at local sites of inflammation promotes inflammation in the periphery. We investigated its effects in the intestinal responses caused by toxin A from Clostridium difficile, the causative agent of antibiotic-associated colitis. Methods: Ileal loops were injected with 10 μg of toxin A, and enterotoxic responses were measured at various time points. Results: Pretreatment of mice with 2.5 μg/kg of the CRH receptor antagonist α-helical CRH(9-41) that blocks both CRH receptor subtypes reduced toxin A-mediated ileal secretion, epithelial cell damage, mucosal edema, neutrophil infiltration, and mucosal content of interleukin 1β and tumor necrosis factor α. Pretreatment with the specific CRH1 receptor antagonist antalarmin (20 mg/kg, IP) also inhibited toxin A-induced fluid secretion and toxin A-associated histologic changes. CRH messenger RNA and protein were increased in mouse ileum 30 minutes after intraluminal toxin A administration. In situ hybridization and immunohistochemistry demonstrated that toxin A at 1 hour caused a substantial increase in the expression of both CRH receptor subtypes in the ileal mucosa. Conclusions: Peripheral CRH may play a proinflammatory role in toxin A-induced intestinal secretion and inflammation and that CRH1 receptor, at least in part, is important in the mediation of these responses.