Effect of adrenomedullin administration on acetic acid-induced colitis in rats

doi:10.1016/j.peptides.2005.05.007

Peptides

Volume 26, Issue 12, December 2005, Pages 2610-2615

https://doi.org/10.1016/j.peptides.2005.05.007 Get rights and content

Abstract

Adrenomedullin (AM) administered intracolonically ameliorated the severity of acetic acid-induced colonic ulceration in rats. Ulcers were induced by subserosal injection of acetic acid into the colon. AM-treated group was administered 0.25–1.0 μg of AM in 0.5 ml of saline intracolonically once a day; the control group received only saline. AM administration dose-dependently and significantly reduced the size of the ulcerative lesions, the associated edema, and the infiltration of the affected area by inflammatory cells. AM also reduced tissue levels of interleukin-6, but not interferon-γ. AM reduces the severity of acetic acid-induced colitis in rats, probably by inhibiting the production and/or release of Th-2 cell-derived factors such as interleukin-6.

Introduction

Although originally isolated from human pheochromocytoma as a vasodilatory peptide [12], adrenomedullin (AM) is now known to have a wide spectrum of other actions, including stimulation of diuresis and natriuresis and several gastrointestinal functions [11], [29]. Among the last, it reportedly exerts a protective effect against experimentally-induced damage to the gastric mucosa [2], [9], [30], [31].

Inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease are now recognized to be caused by crosstalk between a variety of factors. Although the exact nature of its pathogenesis is still uncertain, it has been suggested that a focal immunoreactive disorder and/or dysfunction of the mucosal defence system is involved [27]. Moreover, it is now known that inflammatory cytokines such as interleukin (IL)-1, IL-6, and interferon gamma (IFN-γ) are up-regulated at focal lesions induced by dietary antigen and/or intestinal bacteria [5], [8], [17], [24], [28]. Consequently, the therapeutic strategy for treating IBD now focuses on the use of anti-inflammatory agents [33].

The cytokines found at sites of inflammation are released by T helper (Th) cells that can be divided into two distinct subsets, Th-1 and Th-2, based on the cytokines they express [23]. Characteristically, Th-1 cells produce IL-2 and IFN-γ, whereas Th-2 cells produce IL-4, -5, -6, -9, and -10. In previous studies, the role of Th cell cytokines in the pathogenesis of IBD has been examined using experimental models of colitis induced by intracolonic application of trinitrobenzene sulfonic acid (TNBS) or acetic acid [4], [6], [18], [21], [22]. Our aim in the present study was to investigate the extent to which intracolonic administration of AM would protect the colon in the acetic acid model. We assessed the efficacy of AM by examining its effects on the macroscopic and histological characteristics of the induced lesions, as well as its effects on the levels of Th-1 and Th-2 cytokines in the affected tissues.

Section snippets

Animals and peptide

Male Wistar rats (6–7 weeks old) were used throughout these experiments. The rats were housed under specific pyrogen-free conditions and maintained on standard pellet chow and tap water ad libitum. The recombinant human AM used in this study was provided by Shionogi & Co., Ltd. (Osaka, Japan). All experiments were carried out in accordance with the regulations of the Animal Research Committee of Miyazaki Medical College (no. 2004-077).

Induction of colitis

For 24–36 h prior to inducing colitis, rats were allowed tap

Results

We first evaluated the effect of intracolonic administration of AM on day 5 after application of acetic acid by estimating the mucosal damage in the colon both macroscopically and histologically. We found that the colons of rats in the control group were severely ulcerated by day 5 (Fig. 1a), but that administration of AM (0.25–1.0 μg/day) reduced the size of the lesion in a dose-dependent manner (Figs. 1b and 2). AM significantly (P < 0.05) reduced the severity of the mucosal damage at a dose of

Discussion

Induction of colitis in rats using acetic acid is a classical method used to produce an experimental model of human IBD [7], [18], [20], [32]. A variety of factors involved in the pathogenesis of human IBD, including excessive oxidative stress, enhanced vasopermeability, prolonged neutrophil infiltration, and increased production of inflammatory mediators and cytokines, are also involved in the induction of this animal model [4], [7], [13], [18]. It is presently accepted, therefore, that this

Acknowledgements

This study was supported in part by the grants-in-aid for Scientific Research and for 21st Century Centers of Excellence Program (Life Science) from Ministry of Education, Culture, Sports Science and Technology, Japan, Industrial Technology Research Grant Program in 2003 from New Energy and Industrial Technology Development Organization (NEDO) of Japan, and the Research Grant for translational research for Program for Strategic Regional Science & Technology Advancement.

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Effect of adrenomedullin administration on acetic acid-induced colitis in rats

Abstract

Introduction

Section snippets

Animals and peptide

Induction of colitis

Results

Discussion

Acknowledgements

Peptides

Regul Pept

Biochem Biophys Res Commun

J Biol Chem

Peptides

Gastroenterology

Life Sci

Peptides

Peptides

Gastroenterology

Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo

Nat Med

Specific targeting of IL-6 signalling pathway: a new way to treat IBD?

Gut

Kinetics of cytokine expression during healing of acute colitis in mice

Am J Physiol

The role of interleukin-1 in disease

N Engl J Med

Hapten-induced colitis is associated with colonic patch hypertrophy and T helper cell 2-type responses

J Exp Med

Acetic acid-induced colitis in the rat: a reproducible experimental model for acute ulcerative colitis

Eur Surg Res

Serum levels of soluble CD30 are increased in ulcerative colitis (UC) but not in Crohn's disease (CD)

Clin Exp Immunol