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 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.


CONCLUSIONS
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.
Koga
Hiroyuki
H
Section of Pediatric Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109-0245, USA.
Yang
Hua
H
Adler
Jeremy
J
Zimmermann
Ellen M
EM
Teitelbaum
Daniel H
DH
D000285:Administration, Rectal; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D003094:Collagen / Q000378:metabolism; D003106:Colon / Q000473:pathology*; D016264:Dextran Sulfate; D004305:Dose-Response Relationship, Drug; D015773:Enalaprilat / Q000008:administration & dosage*; D005355:Fibrosis; D053583:Interleukin-1beta / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051785:Smad Proteins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D053583:Interleukin-1beta; D051785:Smad Proteins; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D016264:Dextran Sulfate; D015773:Enalaprilat