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

Surgery. 2008 Aug;144(2):259-68. doi: 10.1016/j.surg.2008.03.043.


Background: We have previously shown that angiotensin converting enzyme-inhibitor (ACE-I) improved colonic inflammation and apoptosis 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 dose-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-beta1 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Rectal
  • Angiotensin-Converting Enzyme Inhibitors / administration & dosage*
  • Animals
  • Colitis / chemically induced
  • Colitis / drug therapy
  • Colitis / pathology*
  • Collagen / metabolism
  • Colon / pathology*
  • Dextran Sulfate
  • Dose-Response Relationship, Drug
  • Enalaprilat / administration & dosage*
  • Fibrosis
  • Interleukin-1beta / metabolism
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Smad Proteins / metabolism
  • Tumor Necrosis Factor-alpha / metabolism


  • Angiotensin-Converting Enzyme Inhibitors
  • Interleukin-1beta
  • Smad Proteins
  • Tumor Necrosis Factor-alpha
  • Collagen
  • Dextran Sulfate
  • Enalaprilat