Role of soluble receptor for advanced glycation end products on endotoxin-induced lung injury.
BACKGROUND
The interaction of receptor for advanced glycation end products (RAGE) and its ligands often leads to inflammatory processes or tissue injury, although the effect of the blockade of RAGE signaling on lung injury remains to be investigated.


OBJECTIVE
Using a murine model of lung injury induced by intratracheal lipopolysaccharide (LPS), we evaluated RAGE expression in the airspace and the effect of recombinant soluble RAGE (sRAGE) on LPS-induced lung injury.


METHODS
First, the expression of sRAGE in bronchoalveolar lavage (BAL) fluid was determined at 24 hours after intratracheal instillation of LPS or phosphate-buffered saline. Next, to evaluate the effect of sRAGE, BAL fluid was collected for cell counting and measurements of lung permeability and cytokine concentrations 24 hours after intratracheal LPS in the mice with or without intraperitoneal administration of sRAGE 1 hour after the instillation. In another series, lungs were sampled for histopathology and detection of apoptotic cells. The activation of nuclear factor (NF)-kappaB was analyzed 4 hours after LPS instillation.


RESULTS
In response to LPS challenge, a RAGE isoform of 48 kD was detected in the BAL fluid. Treatment with sRAGE significantly attenuated the increases in neutrophil infiltration, lung permeability, production of inflammatory cytokines, NF-kappaB activation, and apoptotic cells in the lung as well as development of pathologic changes after LPS instillation.


CONCLUSIONS
RAGE plays an important role in the pathogenesis of LPS-induced lung injury in mice. It was suggested that sRAGE should be tested as a treatment modality in other models of acute lung injury.
Division of Pulmonary Medicine, Keio University School of Medicine, Tokyo, Japan.
Haiying
H
Zhang
Sadatomo
S
Tasaka
Yoshiki
Y
Shiraishi
Koichi
K
Fukunaga
Wakako
W
Yamada
Hiroyuki
H
Seki
Yuko
Y
Ogawa
Keisuke
K
Miyamoto
Yasushi
Y
Nakano
Naoki
N
Hasegawa
Taku
T
Miyasho
Ikuro
I
Maruyama
Akitoshi
A
Ishizaka
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001992:Bronchoalveolar Lavage Fluid; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015633:Extravascular Lung Water / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D018836:Inflammation Mediators / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D020033:Protein Isoforms; D011650:Pulmonary Alveoli / Q000473:pathology / Q000503:physiopathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000008:administration & dosage / Q000502:physiology*; D011994:Recombinant Proteins / Q000008:administration & dosage; D012128:Respiratory Distress Syndrome / Q000473:pathology / Q000503:physiopathology*
D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D020033:Protein Isoforms; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011994:Recombinant Proteins