title: Receptor for advanced glycation end products expressed on alveolar epithelial cells is the main target for hyperoxia-induced lung injury.
abstract: BACKGROUND
  Receptor for advanced glycation end products (RAGE) is abundantly expressed on alveolar epithelial cells (AECs) and participates in innate immune responses such as apoptosis and inflammation. However, it is unclear whether RAGE-mediated apoptosis of AECs is associated with hyperoxia-induced lung injury.
  
  
  METHODS
  We used wild-type and RAGE-knockout C57BL6/J mice in this study. In addition, we developed bone marrow chimeric mouse models expressing RAGE on hematopoietic or non-hematopoietic cells, including lung parenchymal cells, and compared survival ratios and changes in the permeability of the alveolar-capillary barrier after hyperoxia exposure. Further, we prepared single cell suspensions of lung cells and evaluated the apoptosis of AECs or microvascular endothelial cells (MVECs) by using a combination of antibodies and JC-1 dye. We also examined whether RAGE inhibition decreased hyperoxia-induced apoptosis of human lung epithelial cells in vitro.
  
  
  RESULTS
  After hyperoxia exposure, mice expressing RAGE on lung cells showed lower survival rate and increased alveolar-capillary permeability than mice expressing RAGE on hematopoietic cells. RAGE-expressing AECs showed significantly higher apoptosis than RAGE-knockout AECs after in vivo hyperoxia exposure. The level of hyperoxia-induced apoptosis was not different in MVECs. However, RAGE-null lung epithelial cells showed lower apoptosis than RAGE-expressing cells in vitro.
  
  
  CONCLUSIONS
  These results indicated that RAGE on AECs mainly contributed to hyperoxia-induced lung injury and alveolar-capillary barrier disruption.
authors.affiliation: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: chiha-s@mbd.ocn.ne.jp.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Ota
authors.affiliation: Department of Molecular Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: kotaliuishizawa@med.tohoku.ac.jp.
authors.forename: Kota
authors.initials: K
authors.lastname: Ishizawa
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: yamitsu@med.tohoku.ac.jp.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: tando@med.tohoku.ac.jp.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Tando
authors.affiliation: Department of Respiratory Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: hemei5@hotmail.com.
authors.forename: Mei
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: toru_t_res@yahoo.co.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: myamaya@med.tohoku.ac.jp.
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Yamaya
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan. Electronic address: yasuyama@med.kanazawa-u.ac.jp.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan. Electronic address: yamamoto@med.kanazawa-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: kure@med.tohoku.ac.jp.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.affiliation: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: hkubo@med.tohoku.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kubo
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia / Q000150:complications*; D055370:Lung Injury / Q000209:etiology* / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*
chemical_list: D000067759:Receptor for Advanced Glycation End Products
keywords: Alveolar epithelial cells; Alveolar–capillary barrier integrity; Hyperoxia; Microvascular endothelial cells; Receptor for advanced glycation end products