Reduction of Th2 inflammation and fibrosis in eosinophilic esophagitis in a murine model by citri reticulatae pericarpium

Ethnopharmacological relevance: Inflammation and subepithelial fibrosis play major roles in the early pathology of eosinophilic esophagitis (EoE). However, there are currently no pharmacotherapeutic interventions that directly target eosinophilic esophagitis. Citri Reticulatae Pericarpium (CRP, known as Chen-Pi) is one of most frequently used qi-regulating drugs in Chinese medicine and nutrition. CRP is rich with flavonones and polymethoxy fla-vones, both of which exhibit superior anti-inflammatory, anti-allergic and anti-fibrosis effects. This study is to investigate intervention effect of CRP on EoE, to identify its active compounds and to explore its underlying mechanisms. Methods: The CRP extract was obtained by liquid-liquid extraction with 70% ethanol, and its main components were identified by HPLC and TLC chromatography as hesperidin, nobiletin, tangeretin, and narirutin in turn. Furthermore, we evaluated its effect and underlying mechanisms in an PN (Peanut protein extract)-sensitized murine model of food allergy induced EoE. Results: CRP treatment attenuated EoE model mice symptomatology, blocked hypothermia, reduced the pro-duction of PN-specific IgE and IgG1 and T(H)2 cytokines (interleukin (IL)-4 and IL-5), and increased the level of anti-inflammatory cytokines IL-10 and interferon (IFN)-gamma. CRP treatment also significantly alleviated the path-ological damage and reduced fibrosis in inflamed tissues like esophagus, lung, and intestine. These results were strongly associated with reducing the expression of p-p38 mitogen-activated protein kinase (MAPK), trans-forming growth factor beta1 (TGF-beta 1) and p-Smad 3 proteins. Conclusion: CRP extract markedly inhibited T(H)2 immune response and attenuated subepithelial fibrosis with a dose-dependent manner through down-regulating MAPK/TGF-beta signaling pathway. It is suggested that CRP extract might serve as a potential therapy for food allergy-induced EoE like disease.