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Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

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Abstract

Ulcerative colitis is characterized by elevated rates of epithelial cell apoptosis, and an up-regulation of pro-apoptotic cytokines including tumor necrosis factor α (TNF-α). Recently, angiotensin converting enzyme (ACE) has been shown to promote apoptosis. In addition, pharmacologic ACE inhibition (ACE-I) both prevents apoptosis and reduces TNF-α expression in vitro. We hypothesized that ACE-I, using enalaprilat, would decrease colonic epithelial cell apoptosis and reduce colitis severity in the dextran sulfate sodium (DSS)-induced colitis model in mice. We assessed the severity of colitis, and colonic epithelial cell apoptosis, after administration of DSS. Mice were given either daily ACE-I treatment or daily placebo. ACE-I treatment markedly improved clinical outcomes. In addition, ACE-I treatment significantly reduced the maximum histopathologic colitis grade. ACE-I also dramatically reduced the epithelial apoptotic rate. To investigate the mechanism by which ACE-I reduced apoptosis; we measured TNF-α, Bcl-2, and Bax expression. TNF-α mRNA was significantly lower with ACE-I treatment compared to placebo at every time point, as was the ratio of Bax to Bcl-2. We conclude that ACE-I reduces the severity of DSS-induced colitis and reduces epithelial cell apoptosis.

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Acknowledgements

This work was supported by NIH Grant 5 R29 AI44076-01. The paper was presented in part at the 38th Annual Meeting of the Association for Academic Surgery, Houston, Texas, November 11–13, 2004. The authors would like to thank Dr. John Ford for his assistance with the measurement of colonic blood flow.

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Authors and Affiliations

  1. Department of Surgery, Section of Pediatric Surgery, University of Michigan, Ann Arbor, Michigan, 48109, USA

    Ariel U. Spencer, Hua Yang, Emir Q. Haxhija, Barbara E. Wildhaber & Daniel H. Teitelbaum

  2. Department of Pathology, University of Michigan, Ann Arbor, Michigan, 48109, USA

    Joel K. Greenson

  3. Section of Pediatric Surgery, University of Michigan Hospitals, Mott Children’s Hospital, F3970, Ann Arbor, Michigan, 48109-0245, USA

    Daniel H. Teitelbaum

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  1. Ariel U. Spencer
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  2. Hua Yang
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Correspondence to Daniel H. Teitelbaum.

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Spencer, A.U., Yang, H., Haxhija, E.Q. et al. Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition. Dig Dis Sci 52, 1060–1070 (2007). https://doi.org/10.1007/s10620-006-9124-2

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