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.
Similar content being viewed by others
References
Hagiwara C, Tanaka M, Kudo H (2002) Increase in colorectal epithelial apoptotic cells in patients with ulcerative colitis ultimately requiring surgery. J Gastro Hepatol 17:758–764
Boismenu R, Chen Y, Chou K, El-Sheikh A, Buelow R (2002) Orally administered RDP58 reduces the severity of dextran sodium sulphate induced colitis. Ann Rheum Dis 61(Suppl II):ii19–ii24
Vetuschi A, Latella G, Sferra R, Caprilli R, Gaudio E (2002) Increased proliferation and apoptosis of colonic epithelial cells in dextran sulfate sodium-induced colitis in rats. Dig Dis Sci 47:1447–1457
Konstantinos A, Papadakis MD, Targan SR (1999) Current theories on the causes of inflammatory bowel diseases. Gastroenterol Clin North Am 28:283–296
Braegger CP, Nicholls S, Murch SH, Stephens S, MacDonal TT (1992) Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet 339:89–91
Murata Y, Ishiguro Y, Itoh J, Munakata A, Yoshida Y (1995) The role of proinflammatory and immunoregulatory cytokines in the pathogenesis of ulcerative colitis. J Gastroenterol 30(Suppl 8):56–60
Reinecker HC, Steffen M, Witthoeft T, Pflueger I, Schreiber S, MacDermott RP, Raedler A (1993) Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin Exp Immunol 94:174–181
Wang R, Alam G, Zagariya A, Gidea C, Pinillos H, Lalude O, Choudhary G, Oezatalay D, Uhal BD (2000) Apoptosis of lung epithelial cells in response to TNF-α requires angiotensin II generation de novo. J Cell Physiol 185:253–259
Neurath MF, Fuss I, Pasparakis M, Alexopoulou L, Haralambous S, Meyerzum Buschenfeld KH, Strober W, Kollias G (1997) Predominant pathogenic role of tumor necrosis factor in experimental colitis in mice. Eur J Immunol 27:1743–1750
Fiocchi C (1998) Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 115:182–205
Blandino II, Otaka M, Jin M, Komatsu K, Odashima M, Konishi N, Sato T, Kato S, Watanabe S (2001) FR167653, a potent suppressant of interleukin-1 and tumor necrosis factor-alpha production, ameliorates colonic lesions in experimentally induced acute colitis. J Gastroenterol Hepatol 16:1105–1111
Miceli R, Hubert M, Santiago G, Yao D-L, Coleman TA, Huddleston KA, Connolly K (1999) Efficacy of keratinocyte growth factor-2 in dextran sulfate sodium-induced murine colitis. J Pharmacol Exp Ther 290:464–471
Kojouharoff G, Hans W, Obermeier F, Mannel DN, Andus T, Scholmerich J, Gross V, Falk W (1997) Neutralization of tumour necrosis factor (TNF) but not of IL-1 reduces inflammation in chronic dextran sulphate sodium-induced colitis in mice. Clin Exp Immunol 107:353–358
Herfarth H, Brand K, Rath HC, Rogler G, Scholmerich J, Falk W (2000) Nuclear factor-kB activity and intestinal inflammation in dextran sulphate sodium (DSS)-induced colitis in mice is suppressed by gliotoxin. Clin Exp Immunol 120:59–65
Cooper HS, Murthy SNS, Shah RS, Sedergran DJ (1993) Clinicopathologic study of dextran sulfate sodium experimental murine colitis. Lab Invest 69:238–249
Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R (1990) A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology 98:694–702
Egger B, Bajaj-Elliott M, MacDonald TT, Inglin R, Eysselein VE, Buchler MW (2000) Characterisation of acute murine dextran sodium sulphate colitis: cytokine profile and dose dependency. Digestion 62:240–248
Kontoyiannis D, Boulougouris G, Manoloukos M, Armaka M, Apostolaki M, Pizarro T, Kotlyarov A, Forster I, Flavell R, Gaestel M, Tsichlis P, Cominelli F, Kollias G (2002) Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn’s-like inflammatory bowel disease. J Exp Med 196:1563–1574
Yamada T, Horiuchi M, Dzau VJ (1996) Angiotensin II type 2 receptor mediates programmed cell death. Proc Natl Acad Sci USA 93:156–160
Li X, Zhang H, Soledad-Conrad V, Zhuang J, Uhal BD (2003) Bleomycin-induced apoptosis of alveolar epithelial cells requires angiotensin synthesis de novo. Am J Physiol Lung Cell Mol Physiol 284:L501–L507
Chamoux E, Breault L, Lehoux J-G, Gallo-Payet N (1999) Involvement of the angiotensin II type 2 receptor in apoptosis during human fetal adrenal gland development. J Clin Endocrinol Metab 84:4722–4730
Wildhaber BE, Yang H, Haxhija EQ, Spencer AU, Teitelbaum DH (2005) Intestinal intraepithelial lymphocyte derived angiotensin converting enzyme modulates epithelial cell apoptosis. Apoptosis 10(6):1305–1315
Dimmeler S, Rippmann V, Weiland U, Haendeler J, Zeiher AM (1997) Angiotensin II induces apoptosis of human endothelial cells: protective effect of nitric oxide. Circ Res 81:970–976
Burnier M (2001) Angiotensin II type 1 receptor blockers. Circulation 103:904–912
Ehlers MR, Riordan JF (1989) Angiotensin-converting enzyme: new concepts concerning its biological role. Biochemistry 28:5311–5318
Hirasawa K, Sato Y, Hosoda Y, Yamamoto T, Hanai H (2002) Immunohistochemical localization of angiotensin II receptor and local renin-angiotensin system in human colonic mucosa. J Histochem Cytochem 50:275–282
Danilov SM, Faerman AI, Printseva OY, Martynov AV, Sakharov IY, Trakht IN (1987) Immunohistochemical study of angiotensin-converting enzyme in human tissues using monoclonal antibodies. Histochemistry 87:487–490
Duggan KA, Mendelsohn FA, Levens NR (1989) Angiotensin receptors and angiotensin-I converting enzyme in rat intestine. Am J Physiol 257:G504–G510
Sechi LA, Valentin JP, Griffin CA, Schambelan M (1993) Autoradiographic characterization of angiotensin II receptor subtypes in rat intestine. Am J Physiol 265:G21–G27
Yu G, Liang X, Xie X, Su M, Zhao S (2001) Diverse effects of chronic treatment with losartan, fosinopril, and amlodipine on apoptosis, angiotensin II in the left ventricle of hypertensive rats. Int J Cardiol 81:123–129
Wang R, Zagariya A, Ang E, Ibarra-Sunga O, Uhal BD (1999) Fas-induced apoptosis of alveolar epithelial cells requires ANG II generation and receptor interaction. Am J Physiol Lung Cell Mol Physiol 277:L1245–L1250
Goussev A, Sharov VG, Shimoyama H, Tanimura M, Lesch M, Goldstein S, Sabbah HN (1998) Effects of ACE inhibition on cardiomyocyte apoptosis in dogs with heart failure. Am J Physiol Heart Circ Physiol 275:H626–H631
Wang L-X, Ideishi M, Yahiro E, Urata H, Arakawa K, Saku K (2001) Mechanism of the cardioprotective effect of inhibition of the renin-angiotensin system on ischemia/reperfusion-induced myocardial injury. Hypertens Res 24:179–187
Wang R, Zagariya A, Ibarra-Sunga O, Gidea C, Ang E, Deshmukh S, Chaudhary G, Baraboutis J, Filippatos G, Uhal BD (1999) Angiotensin II induces apoptosis in human and rat alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 276:L885–L889
Uhal BD, Gidea C, Bargout R, Bifero A, Ibarra-Sunga O, Papp M, Flynn K, Filippatos G (1998) Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism. Am J Physiol Lung Cell Mol Physiol 275:L1013–L1017
Fujita N, Manabe H, Yoshida N, Matsumoto N, Ochiai J, Masui Y, Uemura M, Naito Y, Yoshikawa T (2000) Inhibition of angiotensin-converting enzyme protects endothelial cell against hypoxia/reoxygenation injury. Biofactors 11:257–266
Shanmugam S, Corvol P, Gasc J-M (1996) Angiotensin II type 2 receptor mRNA expression in the developing cardiopulmonary system of the rat. Hypertension 28:91–97
Nagashima H, Sakomur Y, Yoshikazu A, Uto K, Kameyama K, Ogawa M, Aomi S, Koyanagti H, Ishizuka N, Naruse M, Kawana M, Kasanuki H (2001) Angiotensin II type 2 receptor mediates vascular smooth muscle cell apoptosis in cystic medial degeneration associated with Marfan’s syndrome. Circulation 104(Suppl I):I282–I287
Shenoy UV, Richards EM, Huang X-C, Sumners C (1999) Angiotensin II type 2 receptor-mediated apoptosis of cultured neurons from newborn rat brain. Endocrinology 140:500–509
Yamamoto K, Shioi T, Uchiyama K, Miyamoto T, Sasayama S, Matsumori A (2003) Attenuation of virus-induced myocardial injury by inhibition of the angiotensin II type 1 receptor signal and decreased nuclear factor-kappa B activation in knockout mice. J Am Coll Cardiol 42:2000–2006
Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council (1996) Guide for the care and use of laboratory animals. National Academy Press, Washington, DC (ISBN 0-309-05377-3)
Viney JL (1998) Altering cytokine soups: a recipe for inflammatory bowel disease? Gut 42(5):607–608
Wildhaber BE, Yang H, Teitelbaum DH (2003) Total parenteral nutrition-induced apoptosis in mouse intestinal epithelium: modulation by keratinocyte growth factor. J Surg Res 112:144–151
Sanchez AL, Langdon CM, Akhtar M, Lu J, Richards CD, Bercik P, McKay DM (2003) Adenoviral transfer of the murine oncostatin M gene suppresses dextran-sodium sulfate-induced colitis. J Interferon Cytokine Res 23:193–201
Schindler R, Dinarello CA, Koch K-M (1995) Angiotensin-converting enzyme inhibitors suppress synthesis of tumour necrosis factor and interleukin 1 by human peripheral blood mononuclear cells. Cytokine 7:526–533
Kim S, Izumi Y, Yano M, Hamaguchi A, Miura K, Yamanaka S, Miyazaki H, Iwao H (1998) Angiotensin blockade inhibits activation of mitogen-activated protein kinases in rat balloon-injured artery. Circulation 97:1731–1737
Haendeler J, Ishida M, Hunyady L, Berk BC (2000) The third cytoplasmic loop of the angiotensin II type 1 receptor exerts differential effects on extracellular signal-regulated kinase (ERK1/ERK2) and apoptosis via ras- and Rap1-dependent pathways. Circ Res 86:729–736
Constantinescu CS, Goodman DBP, Ventura ES (1998) Captopril and lisinopril suppress production of interleukin-12 by human peripheral blood mononuclear cells. Immunol Lett 62:25–31
Letizia C, Picarelli A, De Ciocchis A, Di Giovambattista F, Greco M, Cerci S, Torsoli A, Scavo D (1996) Angiotensin-converting enzyme activity in stools of healthy subjects and patients with celiac disease. Dig Dis Sci 41:2268–2271
Guo G, Morrissey J, McCracken R, Tolley T, Liapis H, Klahr S (2001) Contributions of angiotensin II and tumor necrosis factor-α to the development of renal fibrosis. Am J Physiol Renal Physiol 280:F777–F785
Horiuchi M, Yamada T, Hayashida W, Dzau VF (1997) Interferon regulatory factor-1 up-regulates angiotensin II type 2 receptor and induces apoptosis. J Biol Chem 272:11952–11958
Vermes I, Haanen C, Steffens-Nakken H, Reutelingsperger C (1995) Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V. J Immunol Methods 184:39–51
Sandborn WJ, Hanauer SB (1999) Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety. Inflamm Bowel Dis 5:119–133
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254
Suzuki J, Iwai M, Nakagami H, Wu L, Chen R, Sugaya T, Hamada M, Hiwada K, Horiuchi M (2002) Role of angiotensin II-regulated apoptosis through distinct AT1 and AT2 receptors in neointimal formation. Circulation 106:847–853
Wengrower D, Zannineli G, Pappo O, Latella G, Sestieri M, Villanova A, Faitelson Y, Pines M, Goldin E (2004) Prevention of fibrosis in experimental colitis by captopril: the role of tgf-beta1. Inflamm Bowel Dis 10(5):536–545
Inokuchi Y, Morohashi T, Kawana I, Nagashima Y, Kihara M, Umemura S (2005) Amelioration of 2,4,6-trinitrobenzene sulphonic acid induced colitis in angiotensinogen gene knockout mice. Gut 54(3):349–356
Jahovic N, Ercan F, Gedik N, Yuksel M, Sener G, Alican I (2005) The effect of angiotensin-converting enzyme inhibitors on experimental colitis in rats. Regul Pept 15;130(1–2):67–74
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10620-006-9124-2