Skip to main content
SpringerLink
Log in

Angiotensin Converting Enzyme-Inhibitor Reduces Colitis Severity in an IL-10 Knockout Model

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

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.

Aim

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504–1517.

    Article  PubMed  Google Scholar 

  2. Mayer L. Evolving paradigms in the pathogenesis of IBD. J Gastroenterol. 2010;45:9–16.

    Article  PubMed  CAS  Google Scholar 

  3. Duggan KA, Mendelsohn FA, Levens NR. Angiotensin receptors and angiotensin I-converting enzyme in rat intestine. Am J Physiol. 1989;257:G504–G510.

    PubMed  CAS  Google Scholar 

  4. Jaszewski R, Tolia V, Ehrinpreis M, et al. Increased colonic mucosal angiotensin I and II concentrations in Crohn’s colitis. Gastroenterology. 1990;98:1543–1548.

    PubMed  CAS  Google Scholar 

  5. Wildhaber B, Yang H, Haxhija E, et al. Intestinal intraepithelial lymphocyte derived angiotensin converting enzyme modulates epithelial cell apoptosis. Apoptosis. 2005;10:1305–1315.

    Article  PubMed  CAS  Google Scholar 

  6. Spencer A, Yang H, Haxhija E, et al. Reduced severity of a mouse colitis model with angiotensin converting enzyme inhibition. Dig Dis Sci. 2007;52:1060–1070.

    Article  PubMed  CAS  Google Scholar 

  7. Inokuchi Y, Morohashi T, Kawana I, et al. Amelioration of 2, 4, 6-trinitrobenzene sulphonic acid induced colitis in angiotensinogen gene knockout mice. Gut. 2005;54:349–356.

    Article  PubMed  CAS  Google Scholar 

  8. Wengrower D, Zannineli G, Pappo O, et al. Prevention of fibrosis in experimental colitis by captopril: the role of TGF-beta1. Inflamm Bowel Dis. 2004;10:536–545.

    Article  PubMed  Google Scholar 

  9. Strober W, Fuss IJ, Blumberg RS. The immunology of mucosal models of inflammation 1. Annu Rev Immunol. 2002;20:495–549.

    Article  PubMed  CAS  Google Scholar 

  10. Laroui H, Ingersoll SA, Liu HC, et al. Dextran sodium sulfate (DSS) induces colitis in mice by forming nano-lipocomplexes with medium-chain-length fatty acids in the colon. PLoS ONE. 2012;7:e32084.

    Article  PubMed  CAS  Google Scholar 

  11. Kühn R, Löhler J, Rennick D, et al. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75:263–274.

    Article  PubMed  Google Scholar 

  12. Hale LP, Gottfried MR, Swidsinski A. Piroxicam treatment of IL-10-deficient mice enhances colonic epithelial apoptosis and mucosal exposure to intestinal bacteria. Inflamm Bowel Dis. 2005;11:1060–1069.

    Article  PubMed  Google Scholar 

  13. Berg DJ, Davidson N, Kuhn R, et al. Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest. 1996;98:1010–1020.

    Article  PubMed  CAS  Google Scholar 

  14. Davidson NJ, Hudak SA, Lesley RE, et al. IL-12, but not IFN-gamma, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice. J Immunol. 1998;161:3143–3149.

    PubMed  CAS  Google Scholar 

  15. Berg DJ, Zhang J, Weinstock JV, et al. Rapid development of colitis in NSAID-treated IL-10–deficient mice. Gastroenterology. 2002;123:1527–1542.

    Article  PubMed  CAS  Google Scholar 

  16. Rennick DM, Fort MM, Davidson NJ. Studies with IL-10−/− mice: an overview. J Leukoc Biol. 1997;61:389–396.

    PubMed  CAS  Google Scholar 

  17. Haxhija E, Yang H, Spencer A, et al. Modulation of mouse intestinal epithelial cell turnover in the absence of angiotensin converting enzyme. Amer J Physiol Gastroint Liver Physiol. 2008;295:G88–G98.

    Article  CAS  Google Scholar 

  18. Cooper HS. Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest. 1993;69:238–249.

    PubMed  CAS  Google Scholar 

  19. Saverymuttu SH. Indium 111-granulocyte scanning in the assessment of disease extent and disease activity in inflammatory bowel disease. A comparison with colonoscopy, histology, and fecal indium 111-granulocyte excretion. Gastroenterology. 1986;90:1121–1128.

    PubMed  CAS  Google Scholar 

  20. Madsen K, Cornish A, Soper P, et al. Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology. 2001;121:580–591.

    Article  PubMed  CAS  Google Scholar 

  21. Lennernäs H, Nylander S, Ungell AL. Jejunal permeability: a comparison between the using chamber technique and the single-pass perfusion in humans. Pharm Res. 1997;14:667–671.

    Article  PubMed  Google Scholar 

  22. Yang H, Finaly R, Teitelbaum DH. Alteration in epithelial permeability and ion transport in a mouse model of total parenteral nutrition. Crit Care Med. 2003;31:1118–1125.

    Article  PubMed  Google Scholar 

  23. Krug SM, Amasheh S, Richter JF, et al. Tricellulin forms a barrier to macromolecules in tricellular tight junctions without affecting ion permeability. Mol Biol Cell. 2009;20:3713–3724.

    Article  PubMed  CAS  Google Scholar 

  24. Feng Y, Sun X, Yang H, Teitelbaum D. Dissociation of E-cadherin and beta-catenin in a mouse model of total parenteral nutrition: a mechanism for the loss of epithelial cell proliferation and villus atrophy. J Physiol (London). 2009;587:641–654.

    Article  CAS  Google Scholar 

  25. Ahlin P, Kristl J, Kristl A, et al. Investigation of polymeric nanoparticles as carriers of enalaprilat for oral administration. Int J Pharm. 2002;239:113–120.

    Article  PubMed  CAS  Google Scholar 

  26. Okawada M, Koga H, Larsen S, et al. Use of enterally delivered angiotensin II type Ia receptor antagonists to reduce the severity of colitis. Dig Dis Sci. 2011;56:2553–2565.

    Article  PubMed  CAS  Google Scholar 

  27. Liu Z, Zhang P, Ma Y, et al. Lactobacillus plantarum prevents the development of colitis in IL-10-deficient mouse by reducing the intestinal permeability. Mol Biol Rep. 2011;38:1353–1361.

    Article  PubMed  CAS  Google Scholar 

  28. Clayburgh DR, Barrett TA, Tang Y, et al. Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo. J Clin Invest. 2005;115:2702–2715.

    Article  PubMed  CAS  Google Scholar 

  29. Manz M, Vavricka SR, Wanner R, et al. Therapy of steroid-resistant inflammatory bowel disease. Digestion. 2012;1:11–15.

    Article  Google Scholar 

  30. Wildhaber B, Yang H, Coran A, Teitelbaum D. Gene alteration of intestinal intraepithelial lymphocytes in response to massive small bowel resection. Pediatr Surg Int. 2003;19:310–315.

    Article  PubMed  Google Scholar 

  31. Papp M, Li X, Zhuang J, et al. Angiotensin receptor subtype AT(1) mediates alveolar epithelial cell apoptosis in response to ANG II. Am J Physiol Lung Cell Mol Physiol. 2002;282:L713–L718.

    PubMed  CAS  Google Scholar 

  32. Uhal BD, Gidea C, Bargout R, et al. Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism. Am J Physiol. 1998;275:L1013–L1017.

    PubMed  CAS  Google Scholar 

  33. Haxhija EQ, Yang H, Spencer AU, et al. Modulation of mouse intestinal epithelial cell turnover in the absence of angiotensin converting enzyme. Am J Physiol Gastroint Liver Physiol. 2008;295:G88–G98.

    Article  CAS  Google Scholar 

  34. Koga H, Yang H, Adler J, et al. Transanal delivery of angiotensin converting enzyme inhibitor prevents colonic fibrosis in a mouse colitis model: development of a unique mode of treatment. Surgery. 2008;144:259–268.

    Article  PubMed  Google Scholar 

  35. Mizushima T, Sasaki M, Ando T, et al. Blockage of angiotensin II type 1 receptor regulates TNF-α-induced MAdCAM-1 expression via inhibition of NF-κB translocation to the nucleus and ameliorates colitis. Am J Physiol Gastroint Liver Physiol. 2010;298:G255–G266.

    Article  CAS  Google Scholar 

  36. Koga H, Haxhija EQ, Teitelbaum DH. The role of angiotensin II type 1a receptor on intestinal epithelial cells following small bowel resection in a mouse model. Pediatr Surg Int. 2008;24:1279–1286.

    Article  PubMed  Google Scholar 

  37. Hashimoto T, Perlot T, Rehman A, et al. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature. 2012;487:477–481.

    Article  PubMed  CAS  Google Scholar 

  38. Imai Y, Kuba K, Penninger JM. The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice. Exp Physiol. 2008;93:543–548.

    Article  PubMed  CAS  Google Scholar 

  39. Ikenoue Y, Tagami T, Murata M. Development and validation of a novel IL-10 deficient cell transfer model for colitis. Int Immunopharmacol. 2005;5:993–1006.

    Article  PubMed  CAS  Google Scholar 

  40. Pang T, Benicky J, Wang J, et al. Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-gamma activation in human monocytes. J Hypertens. 2012;30:87–96.

    Article  PubMed  CAS  Google Scholar 

  41. Okada Y, Maeda N, Takakura S, et al. Preventive and therapeutic effects of tacrolimus in an interleukin-10-deficient mouse model of colitis. Inflamm Res. 2011;60:1049–1059.

    Article  PubMed  CAS  Google Scholar 

  42. Fiorentino D, Zlotnik A, Mosmann T, et al. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991;147:3815–3822.

    PubMed  CAS  Google Scholar 

  43. Ito K, Takaishi H, Jin Y, et al. Staphylococcal enterotoxin B stimulates expansion of autoreactive T cells that induce apoptosis in intestinal epithelial cells: regulation of autoreactive responses by IL-10. J Immunol. 2000;164:2994–3001.

    PubMed  CAS  Google Scholar 

  44. Nemati F, Rahbar-Roshandel N, Hosseini F, et al. Anti-Inflammatory effects of anti-hypertensive agents: influence on interleukin-1β secretion by peripheral blood polymorphonuclear leukocytes from patients with essential hypertension. Clin Exp Hypertens. 2011;33:66–76.

    Article  PubMed  Google Scholar 

  45. Phillips MI, Kagiyama S. Angiotensin II as a pro-inflammatory mediator. Curr Opin Investig Drugs. 2002;3:569–577.

    PubMed  CAS  Google Scholar 

  46. Miguel-Carrasco J, Zambrano S, Blanca A, et al. Captopril reduces cardiac inflammatory markers in spontaneously hypertensive rats by inactivation of NF-kB. J Inflamm. 2010;7:21.

    Article  Google Scholar 

  47. Nishiyori A, Nagakura Y, Ichikawa K. Piroxicam accelerates development of colitis in T-cell receptor α chain-deficient mice. Eur J Pharmacol. 2009;615:241–245.

    Article  PubMed  CAS  Google Scholar 

  48. Okuda T, Yoshida N, Takagi T, et al. CV-11974, angiotensin II type I receptor antagonist, reduces the severity of indomethacin-induced rat enteritis. Dig Dis Sci. 2008;53:657–663.

    Article  PubMed  CAS  Google Scholar 

  49. Makins R. Gastrointestinal side effects of drugs. Expert Opin Drug Saf. 2003;2:421–429.

    Article  PubMed  CAS  Google Scholar 

  50. Schmidt TD, McGrath KM. Angiotensin-converting enzyme inhibitor angioedema of the intestine: a case report and review of the literature. Am J Med Sci. 2002;324:106–108.

    Article  PubMed  Google Scholar 

  51. Higgins PDR, Davis KJ, Laine L. The epidemiology of ischaemic colitis. Aliment Pharmacol Ther. 2004;19:729–738.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Nathan Opaleski and Pele Browner for their excellent technical assistance. The authors received Grant Support NIH-R01 AI-44076-13, NIH UL1-RR024986 and NIH 1 R43 DK088495-01.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. 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 Sueyoshi, Kathleen M. Woods Ignatoski, Manabu Okawada & Daniel H. Teitelbaum

  2. Biostatistics, Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, MI, USA

    Stephanie Daignault

Authors
  1. Ryo Sueyoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kathleen M. Woods Ignatoski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephanie Daignault
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Manabu Okawada
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel H. Teitelbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel H. Teitelbaum.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10620_2013_2825_MOESM1_ESM.eps

Supplemental: Modified histological colitis scoring system. Images of H&E-stained histomicrographs representing scores from 0 to 5 in our modified scoring system are shown. Examples include a modification of a previously described scoring system whereby a broader scoring of mononuclear infiltration was added to the histological scores [20]. The values for the scoring system are found in Table 1. These images were taken 10× magnifications. (EPS 16032 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sueyoshi, R., Ignatoski, K.M.W., Daignault, S. et al. Angiotensin Converting Enzyme-Inhibitor Reduces Colitis Severity in an IL-10 Knockout Model. Dig Dis Sci 58, 3165–3177 (2013). https://doi.org/10.1007/s10620-013-2825-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-013-2825-4

Keywords

Search

Navigation