Angiotensin converting enzyme-inhibitor reduces colitis severity in an IL-10 knockout model.
BACKGROUND
We previously demonstrated angiotensin converting enzymes (ACE) over-expression in a dextran-sodium sulfate colitis model; ACE inhibitor (ACE-I) treatment reduced colitis severity in this model. However, ACE-I has not been tested in more immunologically relevant colitis models.


OBJECTIVE
We hypothesized that ACE-I would decrease disease severity in an IL-10 knockout (-/-) colitis model.


METHODS
Colitis was induced by giving 10-week old IL-10-/- mice piroxicam (P.O.) for 14 days. The ACE-I enalaprilat was given transanally at a dose of 6.25 mg/kg for 21 days. Prednisolone (PSL) with or without enalaprilat were used as therapeutic, comparative groups. All groups were compared to a placebo treated group. Outcome measures were clinical course, histology, abundance of pro-inflammatory cytokines/chemokines, and epithelial barrier function.


RESULTS
Enalaprilat exhibited better survival (91 %) versus other treatment groups (PSL: 85.7 %, PSL + ACE-I: 71.4 %, placebo: 66.6 %). The ACE-I and PSL + ACE-I groups showed significantly better histological scores versus placebo mice. ACE-I and the PSL groups significantly reduced several pro-inflammatory cytokines versus placebo mice. FITC-dextran permeability was reduced in the ACE-I and PSL + ACE-I groups. Blood pressure was not affected in ACE-I treated mice compared to placebo mice.


CONCLUSIONS
ACE-I was effective in reducing severity of colitis in an IL-10-/- model. The addition of prednisolone minimally augmented this effect. The findings suggest that appropriately dosed ACE-I with or without steroids may be a new therapeutic agent for colitis.
Section of Pediatric Surgery, Department of Surgery, Mott Children's Hospital, University of Michigan, 1540 E. Hospital Dr., SPC 4211, Ann Arbor, MI, 48109-4211, USA.
Ryo
R
Sueyoshi
Kathleen M Woods
KM
Ignatoski
Stephanie
S
Daignault
Manabu
M
Okawada
Daniel H
DH
Teitelbaum
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D015773:Enalaprilat / Q000494:pharmacology*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction
D000806:Angiotensin-Converting Enzyme Inhibitors; D016753:Interleukin-10; D016264:Dextran Sulfate; D015773:Enalaprilat