A keratan sulfate disaccharide prevents inflammation and the progression of emphysema in murine models

Congxiao Gao, Reiko Fujinawa, Takayuki Yoshida, Manabu Ueno, Fumi Ota, Yasuhiko Kizuka, Tetsuya Hirayama, Hiroaki Korekane, Shinobu Kitazume, Toshitaka Maeno, Kazuaki Ohtsubo, Keiichi Yoshida, Yoshiki Yamaguchi, Bernd Lepenies, Jonas Aretz, Christoph Rademacher, Hiroki Kabata, Ahmed E. Hegab, Peter H. Seeberger, Tomoko BetsuyakuKozui Kida, Naoyuki Taniguchi

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)L268-L276
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume312
Issue number2
DOIs
Publication statusPublished - 2016 Dec 21

    Fingerprint

Keywords

  • Chronic obstructive pulmonary disease
  • Glycan
  • Keratan sulfate
  • L4

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology (medical)

Cite this

Gao, C., Fujinawa, R., Yoshida, T., Ueno, M., Ota, F., Kizuka, Y., Hirayama, T., Korekane, H., Kitazume, S., Maeno, T., Ohtsubo, K., Yoshida, K., Yamaguchi, Y., Lepenies, B., Aretz, J., Rademacher, C., Kabata, H., Hegab, A. E., Seeberger, P. H., ... Taniguchi, N. (2016). A keratan sulfate disaccharide prevents inflammation and the progression of emphysema in murine models. American Journal of Physiology - Lung Cellular and Molecular Physiology, 312(2), L268-L276. https://doi.org/10.1152/ajplung.00151.2016