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

Abstract

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.

• Authors: Hiroyuki Koga, Hua Yang, Jeremy Adler, Ellen M Zimmermann, Daniel H Teitelbaum
• Journal: Surgery (Surgery) Vol. 144 Issue 2 Pg. 259-68 (Aug 2008) ISSN: 1532-7361 [Electronic] United States
• PMID: 18656634 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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