Transanal delivery of angiotensin converting enzyme inhibitor prevents colonic fibrosis in a mouse colitis model: development of a unique mode of treatment

Background. We have previously shown that angiotensin converting enzyme-inhibitor (ACE-I) improved colonic inflammation and apoplosis in a dextran sodium sulfate (DSS)-induced colitis model. This study attempted to determine whether ACE-I could, prevent the development of colonic fibrosis. Methods. Colitis was induced in C57BL/6 mice with 2.5 % DSS water for 7 days, followed by 7 days without DSS (fibrosis development). Study groups: Control (naive or non-treated), DSS+Placebo (polyethylene glycol (PEG), and DSS+ACE-I (using enalaprilat and PEG which are not absorbed through intact mucosa): Placebo and ACE-I were delivered daily via transanal route. Colonic mucosal fibrosis and inflammation were evaluated based on histological findings and cytokine expression. Results. Transanal administration of ACE-I/PEG close-dependently decreased the severity of fibrosis and pro-inflammatory cytokine expression. We next investigated if ACE-I acted on the TGF-beta/Smad signaling pathway as a mechanism of this anti fibrosis action. Results showed, a significant down,regulation of TGF-beta 1 expression; as well, downstream signaling of the Smad family, known to mediate fibrosis, showed a decline in Smad 3 and 4 expression with ACE-I/PEG. Conclusion. ACE-I/PEG is effective in preventing colonic fibrosis and pro-inflammatory-cytokine, expression, in. a DSS colitis model, most likely by down-regulating the TGF-beta signaling pathway. ACE-I/ PEG may be a potential new option for treating inflammatory bowel disease.