title: RNA interference targeting carbohydrate sulfotransferase 3 diminishes macrophage accumulation, inhibits MMP-9 expression and promotes lung recovery in murine pulmonary emphysema.
abstract: BACKGROUND
  Chondroitin sulfate proteoglycans are an important mediators in inflammation and leukocyte trafficking. However, their roles in pulmonary emphysema have not been explored. In a murine model of elastase-induced pulmonary emphysema, we found increased carbohydrate sulfotransferase 3 (CHST3), a specific enzyme that synthesizes chondroitin 6-sulfate proteoglycan (C6SPG). To elucidate the role of C6SPG, we investigated the effect of small interfering RNA (siRNA) targeting CHST3 that inhibits C6SPG-synthesis on the pathogenesis of pulmonary emphysema.
  
  
  METHODS
  Mice were intraperitoneally injected with CHST3 siRNA or negative control siRNA on day0 and 7 after intratracheal instillation of elastase. Histology, respiratory function, glycosaminoglycans (GAGs) content, bronchoalveolar lavage (BAL), elastin staining and gene expressions of tumor necrosis factor (TNF)-α and matrix metalloproteinase (MMP)-9 mRNA were evaluated on day7 and/or day21.
  
  
  RESULTS
  CHST3 mRNA increased at day 7 and decreased thereafter in lung. CHST3 siRNA successfully inhibited the expression of CHST3 mRNA throughout the study and this was associated with significant reduction of GAGs and C6SPG. Airway destruction and respiratory function were improved by the treatment with CHST3 siRNA. CHST3 siRNA reduced the number of macrophages both in BAL and lung parenchyma and also suppressed the increased expressions of TNF-α and MMP-9 mRNA. Futhermore, CHST3 siRNA improved the reduction of the elastin in the alveolar walls.
  
  
  CONCLUSIONS
  CHST3 siRNA diminishes accumulation of excessive macrophages and the mediators, leading to accelerate the functional recovery from airway damage by repair of the elastin network associated with pulmonary emphysema.
authors.affiliation: Second Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara-city, Nara, 634-8521, Japan. y-kai@eco.ocn.ne.jp.|Department of Internal Medicine, Yoshino-cho National Health Insurance Yoshino Hospital, 130-1 Oaza Tanji, Yoshino-cho, Yoshino-gun, Nara, 639-3114, Japan. y-kai@eco.ocn.ne.jp.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Kai
authors.affiliation: Second Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara-city, Nara, 634-8521, Japan. ktomoda@naramed-u.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tomoda
authors.affiliation: Stelic Institute & Co., Inc., 1-9-15 Higashi Azabu, Minato-ku, Tokyo, 106-0044, Japan. yoneyama@stelic.co.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoneyama
authors.affiliation: Second Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara-city, Nara, 634-8521, Japan. noriy@naramed-u.ac.jp.
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoshikawa
authors.affiliation: Second Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara-city, Nara, 634-8521, Japan. kimura@naramed-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D004549:Elastin / Q000378:metabolism; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism; D008168:Lung / Q000473:pathology*; D008264:Macrophages / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D011650:Pulmonary Alveoli / Q000473:pathology; D011656:Pulmonary Emphysema / Q000235:genetics* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D020127:Recovery of Function; D015238:Sulfotransferases / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097811:Carbohydrate Sulfotransferases
chemical_list: D004549:Elastin; D006025:Glycosaminoglycans; D020780:Matrix Metalloproteinase 9; D034741:RNA, Small Interfering; D015238:Sulfotransferases; D014409:Tumor Necrosis Factor-alpha; D000097811:Carbohydrate Sulfotransferases; C501830:Mmp9 protein, mouse