title: A keratan sulfate disaccharide prevents inflammation and the progression of emphysema in murine models.
abstract: Emphysema is a typical component of chronic obstructive pulmonary disease (COPD), a progressive and inflammatory airway disease. However, no effective treatment currently exists. Here, we show that keratan sulfate (KS), one of the major glycosaminoglycans produced in the small airway, decreased in lungs of cigarette smoke-exposed mice. To confirm the protective effect of KS in the small airway, a disaccharide repeating unit of KS designated L4 ([SO3--6]Galβ1-4[SO3--6]GlcNAc) was administered to two murine models: elastase-induced-emphysema and LPS-induced exacerbation of a cigarette smoke-induced emphysema. Histological and microcomputed tomography analyses revealed that, in the mouse elastase-induced emphysema model, administration of L4 attenuated alveolar destruction. Treatment with L4 significantly reduced neutrophil influx, as well as the levels of inflammatory cytokines, tissue-degrading enzymes (matrix metalloproteinases), and myeloperoxidase in bronchoalveolar lavage fluid, suggesting that L4 suppressed inflammation in the lung. L4 consistently blocked the chemotactic migration of neutrophils in vitro. Moreover, in the case of the exacerbation model, L4 inhibited inflammatory cell accumulation to the same extent as that of dexamethasone. Taken together, L4 represents one of the potential glycan-based drugs for the treatment of COPD through its inhibitory action against inflammation.
authors.affiliation: Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, Global Research Cluster, Hirosawa, Wako, Saitama, Japan.
authors.forename: Congxiao
authors.initials: C
authors.lastname: Gao
authors.affiliation: Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, Global Research Cluster, Hirosawa, Wako, Saitama, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Fujinawa
authors.affiliation: First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Hokkaido, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Ueno
authors.affiliation: Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, Global Research Cluster, Hirosawa, Wako, Saitama, Japan.
authors.forename: Fumi
authors.initials: F
authors.lastname: Ota
authors.affiliation: Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, Global Research Cluster, Hirosawa, Wako, Saitama, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kizuka
authors.affiliation: Central Research Laboratories, Seikagaku Corporation, Higashiyamato, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hirayama
authors.affiliation: Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, Global Research Cluster, Hirosawa, Wako, Saitama, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Korekane
authors.affiliation: Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, Global Research Cluster, Hirosawa, Wako, Saitama, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Kitazume
authors.affiliation: Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Maeno
authors.affiliation: Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, Global Research Cluster, Hirosawa, Wako, Saitama, Japan.|Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Ohtsubo
authors.affiliation: Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, Global Research Cluster, Hirosawa, Wako, Saitama, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, Global Research Cluster, Hirosawa, Wako, Saitama, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: University of Veterinary Medicine Hannover, Research Center for Emerging Infections and Zoonoses, Infection Immunology, Hannover, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Lepenies
authors.affiliation: Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.|Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Aretz
authors.affiliation: Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.|Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Rademacher
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan; and.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kabata
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan; and.
authors.forename: Ahmed E
authors.initials: AE
authors.lastname: Hegab
authors.affiliation: Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.|Department of Biology, Chemistry and Pharmacy, Freie Universität Berlin, Berlin, Germany.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeberger
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan; and.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Betsuyaku
authors.affiliation: Respiratory Care Clinic, Nippon Medical School, Tokyo, Japan.
authors.forename: Kozui
authors.initials: K
authors.lastname: Kida
authors.affiliation: Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, Global Research Cluster, Hirosawa, Wako, Saitama, Japan; dglycotani@riken.jp.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D003907:Dexamethasone / Q000494:pharmacology; D004187:Disaccharides / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018450:Disease Progression; D007632:Keratan Sulfate / Q000494:pharmacology / Q000627:therapeutic use*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010196:Pancreatic Elastase / Q000378:metabolism; D011014:Pneumonia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D011650:Pulmonary Alveoli / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D011656:Pulmonary Emphysema / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D000067996:RAW 264.7 Cells; D012907:Smoking; D034421:Sus scrofa
chemical_list: D004187:Disaccharides; D003907:Dexamethasone; D007632:Keratan Sulfate; D010196:Pancreatic Elastase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: L4; chronic obstructive pulmonary disease; glycan; keratan sulfate