title: Blockade of receptor for advanced glycation end product attenuates pulmonary reperfusion injury in mice.
abstract: 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.
authors.affiliation: Lung Transplant Program, Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Sternberg
authors.forename: Ram
authors.initials: R
authors.lastname: Gowda
authors.forename: Divya
authors.initials: D
authors.lastname: Mehra
authors.forename: Wu
authors.initials: W
authors.lastname: Qu
authors.forename: Alan
authors.initials: A
authors.lastname: Weinberg
authors.forename: William
authors.initials: W
authors.lastname: Twaddell
authors.forename: Joydeep
authors.initials: J
authors.lastname: Sarkar
authors.forename: Allison
authors.initials: A
authors.lastname: Wallace
authors.forename: Barry
authors.initials: B
authors.lastname: Hudson
authors.forename: Frank
authors.initials: F
authors.lastname: D'Ovidio
authors.forename: Selim
authors.initials: S
authors.lastname: Arcasoy
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Ramasamy
authors.forename: Jeanine
authors.initials: J
authors.lastname: D'Armiento
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Sonett
mesh_terms: 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*
chemical_list: D008024:Ligands; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic