title: Hypoxia promotes danger-mediated inflammation via receptor for advanced glycation end products in cystic fibrosis.
abstract: BACKGROUND
  Hypoxia regulates the inflammatory-antiinflammatory balance by the receptor for advanced glycation end products (RAGE), a versatile sensor of damage-associated molecular patterns. The multiligand nature of RAGE places this receptor in the midst of chronic inflammatory diseases.
  
  
  OBJECTIVE
  To characterize the impact of the hypoxia-RAGE pathway on pathogenic airway inflammation preventing effective pathogen clearance in cystic fibrosis (CF) and elucidate the potential role of this danger signal in pathogenesis and therapy of lung inflammation.
  
  
  METHODS
  We used in vivo and in vitro models to study the impact of hypoxia on RAGE expression and activity in human and murine CF, the nature of the RAGE ligand, and the impact of RAGE on lung inflammation and antimicrobial resistance in fungal and bacterial pneumonia.
  
  
  RESULTS
  Sustained expression of RAGE and its ligand S100B was observed in murine lung and human epithelial cells and exerted a proximal role in promoting inflammation in murine and human CF, as revealed by functional studies and analysis of the genetic variability of AGER in patients with CF. Both hypoxia and infections contributed to the sustained activation of the S100B-RAGE pathway, being RAGE up-regulated by hypoxia and S100B by infection by Toll-like receptors. Inhibiting the RAGE pathway in vivo with soluble (s) RAGE reduced pathogen load and inflammation in experimental CF, whereas sRAGE production was defective in patients with CF.
  
  
  CONCLUSIONS
  A causal link between hyperactivation of RAGE and inflammation in CF has been observed, such that targeting pathogenic inflammation alleviated inflammation in CF and measurement of sRAGE levels could be a useful biomarker for RAGE-dependent inflammation in patients with CF.
authors.affiliation: 1 Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Rossana G
authors.initials: RG
authors.lastname: Iannitti
authors.forename: Andrea
authors.initials: A
authors.lastname: Casagrande
authors.forename: Antonella
authors.initials: A
authors.lastname: De Luca
authors.forename: Cristina
authors.initials: C
authors.lastname: Cunha
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Sorci
authors.forename: Francesca
authors.initials: F
authors.lastname: Riuzzi
authors.forename: Monica
authors.initials: M
authors.lastname: Borghi
authors.forename: Claudia
authors.initials: C
authors.lastname: Galosi
authors.forename: Cristina
authors.initials: C
authors.lastname: Massi-Benedetti
authors.forename: Tim D
authors.initials: TD
authors.lastname: Oury
authors.forename: Lisa
authors.initials: L
authors.lastname: Cariani
authors.forename: Maria
authors.initials: M
authors.lastname: Russo
authors.forename: Luigi
authors.initials: L
authors.lastname: Porcaro
authors.forename: Carla
authors.initials: C
authors.lastname: Colombo
authors.forename: Fabio
authors.initials: F
authors.lastname: Majo
authors.forename: Vincenzina
authors.initials: V
authors.lastname: Lucidi
authors.forename: Ersilia
authors.initials: E
authors.lastname: Fiscarelli
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ricciotti
authors.forename: Cornelia
authors.initials: C
authors.lastname: Lass-Flörl
authors.forename: Luigi
authors.initials: L
authors.lastname: Ratclif
authors.forename: Antonella
authors.initials: A
authors.lastname: Esposito
authors.forename: Fernando Maria
authors.initials: FM
authors.lastname: De Benedictis
authors.forename: Rosario
authors.initials: R
authors.lastname: Donato
authors.forename: Agostinho
authors.initials: A
authors.lastname: Carvalho
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000382:microbiology; D015415:Biomarkers; D015153:Blotting, Western; D003550:Cystic Fibrosis / Q000150:complications / Q000382:microbiology / Q000473:pathology*; D004352:Drug Resistance, Microbial; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000209:etiology / Q000473:pathology*; D018836:Inflammation Mediators / Q000502:physiology*; D007558:Italy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011014:Pneumonia / Q000188:drug therapy / Q000209:etiology* / Q000382:microbiology; D011552:Pseudomonas Infections / Q000382:microbiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000276:immunology*; D020545:Respiratory Mucosa; D046509:Tissue Culture Techniques; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic