The role of the receptor for advanced glycation end-products in lung fibrosis.
The pathogenesis of pulmonary fibrosis remains unclear. The receptor for advanced glycation end-products (RAGE) is a multi-ligand receptor known to be involved in the process of fibrotic change in several organs, such as peritoneal fibrosis and kidney fibrosis. The aim of this study was to examine the contribution of RAGE during the acute inflammation and chronic fibrotic phases of lung injury induced by intratracheal instillation of bleomycin in mice. Bleomycin-induced lung fibrosis was evaluated in wild-type and RAGE-deficient (RAGE-/-) mice. Bleomycin administration to wild-type mice caused an initial pneumonitis that evolved into fibrosis. While RAGE-/- mice developed a similar early inflammatory response, the mice were largely protected from the late fibrotic effects of bleomycin. The protection afforded by RAGE deficiency was accompanied by reduced pulmonary levels of the potent RAGE-inducible profibrotic cytokines transforming growth factor (TGF)-beta and PDGF. In addition, bleomycin administration induced high mobility group box 1 (HMGB-1) production, one of the ligands of RAGE, from inflammatory cells that accumulated within the air space. Coculture with HMGB-1 induced epithelial-mesenchymal transition (EMT) in alveolar type II epithelial cells from wild-type mice. However, alveolar type II epithelial cells derived from RAGE-/- mice did not respond to HMGB-1 treatment, such that the RAGE/HMGB-1 axis may play an important role in EMT. Also, bleomycin administration induced profibrotic cytokines TGF-beta and PDGF only in wild-type mouse lungs. Our results suggested that RAGE contributes to bleomycin-induced lung fibrosis through EMT and profibrotic cytokine production. Thus, RAGE may be a new therapeutic target for pulmonary fibrosis.
He
Mei
M
Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Sendai, Japan.
Kubo
Hiroshi
H
Ishizawa
Kota
K
Hegab
Ahmed E
AE
Yamamoto
Yasuhiko
Y
Yamamoto
Hiroshi
H
Yamaya
Mutsuo
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001761:Bleomycin / Q000008:administration & dosage; D001772:Blood Cell Count; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002454:Cell Differentiation / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D024243:HMGB1 Protein / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000378:metabolism*; D015996:Survival Rate; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D024243:HMGB1 Protein; D010982:Platelet-Derived Growth Factor; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D053773:Transforming Growth Factor beta1; D001761:Bleomycin