Original Article
Copyright ©2010 Baishideng. All rights reserved.
World J Gastroenterol. Jun 21, 2010; 16(23): 2873-2880
Published online Jun 21, 2010. doi: 10.3748/wjg.v16.i23.2873
CXCR4 antagonist AMD3100 attenuates colonic damage in mice with experimental colitis
Xian-Ming Xia, Fang-Yu Wang, Wen-An Xu, Zhen-Kai Wang, Jiong Liu, You-Ke Lu, Xin-Xin Jin, Heng Lu, Yun-Zhu Shen
Xian-Ming Xia, Fang-Yu Wang, Wen-An Xu, Zhen-Kai Wang, Jiong Liu, You-Ke Lu, Xin-Xin Jin, Heng Lu, Yun-Zhu Shen, Department of Gastroenterology and Hepatology, Jinling Hospital, Nanjing 210002, Jiangsu Province, China
Author contributions: Xia XM and Wang FY designed the research; Xia XM, Wang ZK, Lu H and Shen YZ performed the experiments; Liu J and Lu YK provided the analytic tools and edited the manuscript; Xu WA and Jin XX analyzed the data; Xia XM and Wang FY wrote the paper.
Supported by The Postdoctoral Science Foundation of China, No. 20090451573 and Postdoctoral Science Foundation of Jiangsu Province, No. 0902061C
Correspondence to: Fang-Yu Wang, Professor, Department of Gastroenterology and Hepatology, Jinling Hospital, 305 Zhongshan East Road, Nanjing 210002, Jiangsu Province, China. wangfy65@gmail.com
Telephone: +86-25-80860051 Fax: +86-25-80860151
Received: March 8, 2010
Revised: April 5, 2010
Accepted: April 12, 2010
Published online: June 21, 2010
Abstract

AIM: To investigate the effects of the chemokine stromal cell-derived factor-1 (CXCL12) receptor (CXCR4) antagonist AMD3100 on colonic inflammation and epithelial barrier in dextran sulfate sodium (DSS)-induced colitis in mice.

METHODS: Experimental colitis was induced by administration of 5% DSS for 7 d, and assays performed on intestinal segments from the ileocecal valve to the anus. Colonic morphology was examined by hematoxylin and eosin staining. Colonic cytokines were determined by enzyme-linked immunosorbent assay. Myeloperoxidase (MPO) activity (indicator of inflammatory infiltration) was observed spectrophotometrically. Gut permeability was assessed by mucosal-to-serosal clearance of fluorescein isothiocyanate-conjugated dextran 4000 (FD4) in everted gut sacs. The apoptosis of colonic epithelium was assessed by Hoechst-33342 staining. To further elucidate the role of CXCR4 in colonic inflammation, we also investigated the effect of AMD3100 on migration and cytokine production of isolated peripheral blood mononuclear cells (PBMCs).

RESULTS: DSS-induced colitis was characterized by morphologic changes, as well as increased colonic cytokines, inflammatory infiltration, epithelial apoptosis, and intestinal permeability in mice. In AMD3100-treated mice, epithelial destruction, inflammatory infiltration, and submucosal edema were markedly reduced; colonic tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interferon-γ (IFN-γ) levels, as well as MPO activity were significantly decreased. Increased intestinal permeability in DSS-treated mice was significantly reduced by AMD3100. The number of apoptotic cells in colitis mice was markedly increased after DSS administration, and decreased when treated with the CXCR4 antagonist AMD3100. In pre-activated PBMCs, CXCL12 stimulation significantly increased the migration of PBMCs, and was inhibited by AMD3100. Moderately increased TNF-α, IL-6, and IFN-γ from CXCL12-treated PBMCs were also reduced by AMD3100.

CONCLUSION: The CXCR4 antagonist AMD3100 exerts therapeutic effects on experimental colitis by inhibiting colonic inflammation and enhancing epithelial barrier integrity.

Keywords: Ulcerative colitis; Chemokine stromal cell-derived factor-1 receptor; Inflammation; Apoptosis; Intestinal permeability; Epithelial barrier