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      The synthetic hydroxyproline-containing collagen analogue (Gly-Pro-Hyp) 10 ameliorates acute DSS colitis

      1 , 6 , * , 2 , 3 , 3 , 4 , 1 , 5 , 1 , 1 , 4 , 4 , 4
      European Journal of Microbiology and Immunology
      Akadémiai Kiadó, co-published with Springer Science+Business Media B.V., Formerly Kluwer Academic Publishers B.V.
      (GPO)10 , matrix metalloproteinases, gelatinase, proMMP-2, extracellular matrix, acute DSS colitis, intestinal inflammation, pro-inflammatory cytokines, IL-10, proliferation, in vivo , extra-intestinal immune responses, lung, human IBD, crinopexy, (GPO)10, (Gly-Pro-Hyp)10 , PBS, phosphate buffered saline, DSS, dextrane sulfate sodium, p.i., post induction, MMP, matrix metalloproteinase, IBD, inflammatory bowel disease, i.p., intraperitoneal, p.o., peroral, MT-MMP, membrane-type matrix metalloproteinase, TIMP, tissue inhibitor of matrix metalloproteinases, TNF, tumor necrosis factor, IFN, interferon, Treg, regulatory T cell, Th, T helper, IL, interleukin, SPF, specific pathogen-free, HE, hematoxylin eosin, MLN, mesenteric lymphnodes

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          In experimental models of and humans with intestinal inflammation, increased levels of the matrix-degrading gelatinases MMP-2 and -9 in inflamed tissues can be detected. The synthetic collagen analogue (Gly-Pro-Hyp) 10, (GPO) 10, has been identified as a relevant binding structure for proMMP-2/-9 and promotes enzymatic activity of proMMP-2. Since targeted MMP strategies might offer promising anti-inflammatory treatment options, we for the first time studied in vivo actions exerted by (GPO) 10 applying an acute dextrane sulfate sodium (DSS) induced colitis model. Seven-day intraperitoneal (GPO) 10 treatment ameliorated clinical symptoms and histopathological colonic changes as compared to placebo controls with severe colitis. (GPO) 10-treated mice displayed a diminished influx of neutrophils, and T- and B-lymphocytes into their colonic mucosa whereas numbers of regulatory T-cells and regenerative cells were higher as compared to placebo controls. Furthermore, IL-6 secretion was down-regulated in ex vivo colonic biopsies derived from (GPO) 10-treated mice whereas higher concentrations of the anti-inflammatory cytokine IL-10 in extra-intestinal compartments such as MLN and spleen could be detected. Strikingly, influx of inflammatory cells into lungs was abolished following (GPO) 10 application. We therefore propose (GPO) 10 as a promising effective and safe treatment option of intestinal and extra-intestinal inflammatory conditions in humans.

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          Most cited references44

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          Matrix metalloproteinases: biologic activity and clinical implications.

          Tumor progression is a complex, multistage process by which a normal cell undergoes genetic changes that result in phenotypic alterations and the acquisition of the ability to spread and colonize distant sites in the body. Although many factors regulate malignant tumor growth and spread, interactions between a tumor and its surrounding microenvironment result in the production of important protein products that are crucial to each step of tumor progression. The matrix metalloproteinases (MMPs) are a family of degradative enzymes with clear links to malignancy. These enzymes are associated with tumor cell invasion of the basement membrane and stroma, blood vessel penetration, and metastasis. They have more recently been implicated in primary and metastatic tumor growth and angiogenesis, and they may even have a role in tumor promotion. This review outlines our current understanding of the MMP family, including the association of particular MMPs with malignant phenotypes and the role of MMPs in specific steps of the metastatic cascade. As scientific understanding of the MMPs has advanced, therapeutic strategies that capitalize on blocking the enzymes have rapidly developed. The preclinical and clinical evolution of the synthetic MMP inhibitors (MMPIs) is also examined, with the discussion encompassing important methodologic issues associated with determining clinical efficacy of MMPIs and other novel therapeutic agents.
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            Gram-negative bacteria aggravate murine small intestinal Th1-type immunopathology following oral infection with Toxoplasma gondii.

            Oral infection of susceptible mice with Toxoplasma gondii results in Th1-type immunopathology in the ileum. We investigated gut flora changes during ileitis and determined contributions of gut bacteria to intestinal inflammation. Analysis of the intestinal microflora revealed that ileitis was accompanied by increasing bacterial load, decreasing species diversity, and bacterial translocation. Gram-negative bacteria identified as Escherichia coli and Bacteroides/Prevotella spp. accumulated in inflamed ileum at high concentrations. Prophylactic or therapeutic administration of ciprofloxacin and/or metronidazole ameliorated ileal immunopathology and reduced intestinal NO and IFN-gamma levels. Most strikingly, gnotobiotic mice in which cultivable gut bacteria were removed by quintuple antibiotic treatment did not develop ileitis after Toxoplasma gondii infection. A reduction in total numbers of lymphocytes was observed in the lamina propria of specific pathogen-free (SPF), but not gnotobiotic, mice upon development of ileitis. Relative numbers of CD4(+) T cells did not differ in naive vs infected gnotobiotic or SPF mice, but infected SPF mice showed a significant increase in the frequencies of activated CD4(+) T cells compared with gnotobiotic mice. Furthermore, recolonization with total gut flora, E. coli, or Bacteroides/Prevotella spp., but not Lactobacillus johnsonii, induced immunopathology in gnotobiotic mice. Animals recolonized with E. coli and/or total gut flora, but not L. johnsonii, showed elevated ileal NO and/or IFN-gamma levels. In conclusion, Gram-negative bacteria, i.e., E. coli, aggravate pathogen-induced intestinal Th1-type immunopathology. Thus, pathogen-induced acute ileitis may prove useful to study bacteria-host interactions in small intestinal inflammation and to test novel therapies based on modulation of gut flora.
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              Matrix Metalloproteinases: A Review

              Matrix metalloproteinases (MMPs) are a family of nine or more highly homologous Zn(++)-endopeptidases that collectively cleave most if not all of the constituents of the extracellular matrix. The present review discusses in detail the primary structures and the overlapping yet distinct substrate specificities of MMPs as well as the mode of activation of the unique MMP precursors. The regulation of MMP activity at the transcriptional level and at the extracellular level (precursor activation, inhibition of activated, mature enzymes) is also discussed. A final segment of the review details the current knowledge of the involvement of MMP in specific developmental or pathological conditions, including human periodontal diseases.

                Author and article information

                European Journal of Microbiology and Immunology
                Akadémiai Kiadó, co-published with Springer Science+Business Media B.V., Formerly Kluwer Academic Publishers B.V.
                1 September 2012
                : 2
                : 3
                : 192-200
                [ 1 ] Institute of Microbiology and Hygiene, Charité, University Medicine Berlin, Berlin, Germany
                [ 2 ] Department of Biotechnology, Institute for Biochemistry and Biology, University of Potsdam, Potsdam, Germany
                [ 3 ] Department of Pathology/Research Center ImmunoSciences (RCIS), Charité University Medicine Berlin, Berlin, Germany
                [ 4 ] Department of Internal Medicine, Charité, University Medicine Berlin, Berlin, Germany
                [ 5 ] Department of Biochemistry, University of Cambridge, Cambridge, UK
                [ 6 ] Department of Micro biology and Hygiene, University Medicine Berlin, CC5, Campus Benjamin Franklin, Hindenburgdamm 27, D-12203, Berlin, Germany
                Author notes
                [* ] +49-30-8445-3739, +49-30-450-524-902, markus.heimesaat@ 123456charite.de
                Original Articles

                Medicine,Immunology,Health & Social care,Microbiology & Virology,Infectious disease & Microbiology
                IL-10,matrix metalloproteinases,gelatinase,proMMP-2,extracellular matrix,acute DSS colitis,(GPO)10 ,intestinal inflammation,pro-inflammatory cytokines,proliferation, in vivo ,extra-intestinal immune responses,lung,human IBD,crinopexy,(GPO)10, (Gly-Pro-Hyp)10 ,PBS, phosphate buffered saline,DSS, dextrane sulfate sodium,p.i., post induction,MMP, matrix metalloproteinase,IBD, inflammatory bowel disease,i.p., intraperitoneal,p.o., peroral,MT-MMP, membrane-type matrix metalloproteinase,TIMP, tissue inhibitor of matrix metalloproteinases,TNF, tumor necrosis factor,IFN, interferon, Treg, regulatory T cell,Th, T helper,IL, interleukin,SPF, specific pathogen-free,HE, hematoxylin eosin,MLN, mesenteric lymphnodes


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