title: Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis.
abstract: Recent studies have implicated a pathogenic role for matrix metalloproteinases 9 (MMP-9) in inflammatory bowel disease. Although loss of epithelial barrier function has been shown to be a key pathogenic factor for the development of intestinal inflammation, the role of MMP-9 in intestinal barrier function remains unclear. The aim of this study was to investigate the role of MMP-9 in intestinal barrier function and intestinal inflammation. Wild-type (WT) and MMP-9(-/-) mice were subjected to experimental dextran sodium sulfate (DSS) colitis by administration of 3% DSS in drinking water for 7 days. The mouse colonic permeability was measured in vivo by recycling perfusion of the entire colon using fluorescently labeled dextran. The DSS-induced increase in the colonic permeability was accompanied by an increase in intestinal epithelial cell MMP-9 expression in WT mice. The DSS-induced increase in intestinal permeability and the severity of DSS colitis was found to be attenuated in MMP-9(-/-) mice. The colonic protein expression of myosin light chain kinase (MLCK) and phospho-MLC was found to be significantly increased after DSS administration in WT mice but not in MMP-9(-/-) mice. The DSS-induced increase in colonic permeability and colonic inflammation was attenuated in MLCK(-/-) mice and MLCK inhibitor ML-7-treated WT mice. The DSS-induced increase in colonic surface epithelial cell MLCK mRNA was abolished in MMP-9(-/-) mice. Lastly, increased MMP-9 protein expression was detected within the colonic surface epithelial cells in ulcerative colitis cases. These data suggest a role of MMP-9 in modulation of colonic epithelial permeability and inflammation via MLCK.
authors.affiliation: Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico;
authors.forename: Prashant
authors.initials: P
authors.lastname: Nighot
authors.affiliation: Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico;
authors.forename: Rana
authors.initials: R
authors.lastname: Al-Sadi
authors.affiliation: Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; TMa@salud.unm.edu.
authors.forename: Manmeet
authors.initials: M
authors.lastname: Rawat
authors.affiliation: Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico;
authors.forename: Shuhong
authors.initials: S
authors.lastname: Guo
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois; and.
authors.forename: D Martin
authors.initials: DM
authors.lastname: Watterson
authors.affiliation: Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; Veterans Affairs Medical Center, Albuquerque, New Mexico.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ma
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D003106:Colon / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010539:Permeability; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012720:Severity of Illness Index; D015398:Signal Transduction; D062725:Tight Junction Proteins / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D013997:Time Factors
chemical_list: D018994:Myosin Light Chains; D047428:Protein Kinase Inhibitors; D062725:Tight Junction Proteins; D016264:Dextran Sulfate; D009219:Myosin-Light-Chain Kinase; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: matrix metalloproteinase; myosin light chain kinase; tight junction