Blockade of the renin-angiotensin system prevents acute and immunologically relevant colitis in murine models.
BACKGROUND
Blockade of the renin-angiotensin system (RAS) has been shown to alleviate inflammatory processes in the gastrointestinal tract. The aim of this study was to determine if blockade of the RAS would be effective in an immunologically relevant colitis model, and to compare outcome with an acute colitis model.


METHODS
A losartan analog, CCG-203025 (C23H26ClN3O5S) containing a highly polar sulfonic acid moiety that we expected would allow localized mucosal antagonism with minimal systemic absorption was selected as an angiotensin II type 1a receptor antagonist (AT1aR-A). Two colitis models were studied: (1) Acute colitis was induced in 8- to 10-week-old C57BL/6J mice by 2.5 % dextran sodium sulfate (DSS, in drinking water) for 7 days. (2) IL10-/-colitis Piroxicam (200 ppm) was administered orally in feed to 5-week-old IL-10-/-mice (C57BL/6J background) for 14 days followed by enalaprilat (ACE-I), CCG-203025 or PBS administered transanally for 14 days.


RESULTS
In the DSS model, weight loss and histologic score for CCG-203025 were better than with placebo. In the IL10-/-model, ACE-I suppressed histologic damage better than CCG-203025. Both ACE-I and CCG-203025 reduced pro-inflammatory cytokines and chemokines.


CONCLUSIONS
This study demonstrated the therapeutic efficacy of both ACE-I and AT1aR-A for preventing the development of both acute and immunologically relevant colitis.
Section of Pediatric Surgery, Department of Surgery, The University of Michigan Medical School, Mott Children's Hospital, F3970, Ann Arbor, MI, 48109-0245, USA. manabu-o@juntendo.ac.jp.|Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. manabu-o@juntendo.ac.jp.
Manabu
M
Okawada
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109-1065, USA.
Michael W
MW
Wilson
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109-1065, USA.
Scott D
SD
Larsen
Therapeutic Systems Research Laboratories, Inc, Ann Arbor, MI, 48108, USA.
Elke
E
Lipka
Therapeutic Systems Research Laboratories, Inc, Ann Arbor, MI, 48108, USA.
John
J
Hillfinger
Section of Pediatric Surgery, Department of Surgery, The University of Michigan Medical School, Mott Children's Hospital, F3970, Ann Arbor, MI, 48109-0245, USA.
Daniel H
DH
Teitelbaum
D000208:Acute Disease; D047228:Angiotensin II Type 1 Receptor Blockers / Q000276:immunology / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000276:immunology / Q000494:pharmacology; D000818:Animals; D003092:Colitis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D016861:Cyclooxygenase Inhibitors / Q000276:immunology / Q000494:pharmacology; D004195:Disease Models, Animal; D015773:Enalaprilat / Q000276:immunology / Q000494:pharmacology; D019808:Losartan / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010894:Piroxicam / Q000276:immunology / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000276:immunology
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D016861:Cyclooxygenase Inhibitors; D010894:Piroxicam; D015773:Enalaprilat; D019808:Losartan
Angiotensin II type Ia receptor; Angiotensin II type Ia receptor antagonist; Angiotensin converting enzyme; Colitis; Dextran sodium sulfate; IL10
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