Blockade of receptor for advanced glycation end product attenuates pulmonary reperfusion injury in mice.
OBJECTIVE
The receptor for advanced glycation end products (RAGE) is expressed at high levels in the lung, particularly in type 1 alveolar cells, and has been shown to amplify injury triggered by acute stress. Previous studies suggest serum concentrations of soluble RAGE increase during pulmonary reperfusion injury after transplantation. RAGE blockade has been shown to suppress hepatic and cardiac ischemia and reperfusion injury in mice. Thus we tested the hypothesis that RAGE mediates tissue-injury mechanisms in ischemia and reperfusion injury in the lung.


METHODS
C57BL/6 mice were subjected to 30 minutes of pulmonary ischemia by clamping the left hilum, followed by 60 minutes of reperfusion. Lung function was assessed by means of blood gas analysis, and capillary leak was assessed by injecting fluorescein isothiocyanate-labeled albumin and comparing fluorescence in bronchial lavage fluid with that in serum. Histologic analysis of the lung was performed by a pathologist naive to the experimental conditions.


RESULTS
In animals subjected to RAGE blockade, significant increases in Po(2) (108 vs 73 mm Hg, P = .0094) and more than 3-fold decrease in capillary leak Relative Fluorescent Units (RFU, 6.12 vs 1.75; P = .001) were observed. Histologic examination revealed significant injury reduction in soluble RAGE-treated animals versus control animals. RAGE knockout mice exhibited a protected phenotype when exposed to pulmonary ischemia and reperfusion. Additionally, interleukin 8 production and nuclear factor kappaB activation were increased in control mice.


CONCLUSIONS
Abrogation of RAGE signaling attenuates pulmonary ischemia and reperfusion injury. This study suggests that RAGE might play a central role in pulmonary reperfusion injury and in transplantation and that blockade of RAGE might offer a potential target to abrogate pulmonary reperfusion injury in clinical transplantation.
Sternberg
David I
DI
Lung Transplant Program, Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Gowda
Ram
R
Mehra
Divya
D
Qu
Wu
W
Weinberg
Alan
A
Twaddell
William
W
Sarkar
Joydeep
J
Wallace
Allison
A
Hudson
Barry
B
D'Ovidio
Frank
F
Arcasoy
Selim
S
Ramasamy
Ravichandran
R
D'Armiento
Jeanine
J
Schmidt
Ann Marie
AM
Sonett
Joshua R
JR
D000818:Animals; D004195:Disease Models, Animal; D007511:Ischemia / Q000150:complications; D008024:Ligands; D008168:Lung / Q000098:blood supply / Q000473:pathology; D008171:Lung Diseases / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000008:administration & dosage* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*
D008024:Ligands; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic