Disruption of intestinal barrier function may be a common pathogenetic mechanism that mediates morbidity and mortality in subjects with inflammatory bowel disease (IBD) and gut-derived sepsis (GDS). If so, a therapeutic strategy that protects mucosal barrier function and structure by increasing accumulation of tight and adhesion junction proteins that connect mucosal epithelial cells could be used to treat these conditions. We recently characterized a novel 18-kDa protein called AMP-18, that is synthesized in epithelial cells of the gastric antrum mucosa of humans and 6 other mammals, and has mitogenic and motogenic properties. A 21-mer peptide derived from the central domain of the protein was found to be cytoprotective in human colonic epithelial cell (Caco-2/bbe) cultures subjected to injury by an oxidant, indomethacin, or dextran sulfate sodium (DSS) used to induce colitis in mice, Studies in cell culture indicate that this AMP peptide activates p38 MAP kinase, increases accumulation of specific tight junction proteins (occludin, ZO-1, claudin-5), an adherens junction protein (E-cadherin), and heat shock proteins (hsp25, hsp72), and protects the actin microfilament network in cells exposed to cytochalasin D. When given to mice, AMP peptide increases the content of hyperphosphorylated occludin in the colonic mucosa. To determine if these biological effects of AMP peptide confer colonic cytoprotection in vivo, its effectiveness was tested in two important animal models of barrier compromise, IBD and GDS. Pretreatment of mice with AMP peptide delayed the onset of bloody diarrhea and reduced weight loss in animals given DSS to induce colitis. The peptide also prevented the death of mice given intracecal Pseudomonas aeruginosa following the surgical stress of partial hepatectomy and post-operative food deprivation in a model GDS. Our objective is to obtain additional support in cell culture and in vivo models of IBD and GDS to demonstrate that AMP peptide, by increasing accumulation of tight junction proteins such as occludin, protects colonic mucosal barrier structure and function. Studies that confirm and extend the cytoprotective, mitogenic, and motogenic effects of AMP peptide would lend further support to developing this molecule as a therapeutic agent to treat not only IBD and GDS, but other GI diseases mediated by disruption of intestinal tight junctions and the subsequent increase in mucosal permeability to bacteria and their products.
| Walsh-Reitz, Margaret M; Huang, Erick F; Musch, Mark W et al. (2005) AMP-18 protects barrier function of colonic epithelial cells: role of tight junction proteins. Am J Physiol Gastrointest Liver Physiol 289:G163-71 |
