CXCR4 antagonist AMD3100 attenuates colonic damage in mice with experimental colitis

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 signif icantly 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 signif icantly 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.