Article: article from journal or magazin.
Reduced severity of a mouse colitis model with angiotensin converting enzyme inhibition.
Digestive Diseases and Sciences
Publication types: Journal Article ; Research Support, N.I.H., Extramural Publication Status: ppublish
Ulcerative colitis is characterized by elevated rates of epithelial cell apoptosis, and an up-regulation of pro-apoptotic cytokines including tumor necrosis factor alpha (TNF-alpha). Recently, angiotensin converting enzyme (ACE) has been shown to promote apoptosis. In addition, pharmacologic ACE inhibition (ACE-I) both prevents apoptosis and reduces TNF-alpha 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-alpha, Bcl-2, and Bax expression. TNF-alpha 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.
Angiotensin-Converting Enzyme Inhibitors/pharmacology, Animals, Apoptosis/drug effects, Colitis/chemically induced, Colitis/metabolism, Colon/blood supply, Colon/metabolism, Dextran Sulfate, Enalaprilat/pharmacology, Epithelial Cells/drug effects, Epithelial Cells/pathology, Flow Cytometry, Intestinal Mucosa/blood supply, Intestinal Mucosa/metabolism, Male, Mice, Mice, Inbred C57BL, Peptidyl-Dipeptidase A/metabolism, Proto-Oncogene Proteins c-bcl-2/metabolism, Regional Blood Flow/drug effects, Tumor Necrosis Factor-alpha/metabolism, bcl-2-Associated X Protein/metabolism
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