Receptor for advanced glycation end products expressed on alveolar epithelial cells is the main target for hyperoxia-induced lung injury

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• 作者：Chiharu Ota ; M.D. ; Ph.D.^a ; ^b ; ^{chiha-s@mbd.ocn.ne.jp" class="auth_mail" title="E-mail the corresponding author} ; Kota Ishizawa^c ; ^{kotaliuishizawa@med.tohoku.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Mitsuhiro Yamada^d ; ^{yamitsu@med.tohoku.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Yukiko Tando^a ; ^{tando@med.tohoku.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Mei He^e ; ^{hemei5@hotmail.com" class="auth_mail" title="E-mail the corresponding author} ; Toru Takahashi^a ; ^{toru_t_res@yahoo.co.jp" class="auth_mail" title="E-mail the corresponding author} ; Mutsuo Yamaya^a ; ^{myamaya@med.tohoku.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Yasuhiko Yamamoto^f ; ^{yasuyama@med.kanazawa-u.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Hiroshi Yamamoto^f ; ^{yamamoto@med.kanazawa-u.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Shigeo Kure^b ; ^{kure@med.tohoku.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Hiroshi Kubo^a ; ^{hkubo@med.tohoku.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Receptor for advanced glycation end products ; Alveolar epithelial cells ; Microvascular endothelial cells ; Hyperoxia ; Alveolar&ndash ; capillary barrier integrity
• 刊名：Respiratory Investigation
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：54
• 期：2
• 页码：98-108
• 全文大小：5428 K

文摘

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.

Conclusion

These results indicated that RAGE on AECs mainly contributed to hyperoxia-induced lung injury and alveolar–capillary barrier disruption.