title: The receptor for advanced glycation end products in ventilator-induced lung injury.
abstract: BACKGROUND
  Mechanical ventilation (MV) can cause ventilator-induced lung injury (VILI). The innate immune response mediates this iatrogenic inflammatory condition. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that can amplify immune and inflammatory responses. We hypothesized that RAGE signaling contributes to the pro-inflammatory state induced by MV.
  
  
  METHODS
  RAGE expression was analyzed in lung brush and lavage cells obtained from ventilated patients and lung tissue of ventilated mice. Healthy wild-type (WT) and RAGE knockout (KO) mice were ventilated with relatively low (approximately 7.5 ml/kg) or high (approximately 15 ml/kg) tidal volume. Positive end-expiratory pressure was set at 2 cm H2O during both MV strategies. Also, WT and RAGE KO mice with lipopolysaccharide (LPS)-induced lung injury were ventilated with the above described ventilation strategies. In separate experiments, the contribution of soluble RAGE, a RAGE isoform that may function as a decoy receptor, in ventilated RAGE KO mice was investigated. Lung wet-to-dry ratio, cell and neutrophil influx, cytokine and chemokine concentrations, total protein levels, soluble RAGE, and high-mobility group box 1 (HMGB1) presence in lung lavage fluid were analyzed.
  
  
  RESULTS
  MV was associated with increased RAGE mRNA levels in both human lung brush samples and lung tissue of healthy mice. In healthy high tidal volume-ventilated mice, RAGE deficiency limited inflammatory cell influx. Other VILI parameters were not affected. In our second set of experiments where we compared RAGE KO and WT mice in a 2-hit model, we observed higher pulmonary cytokine and chemokine levels in RAGE KO mice undergoing LPS/high tidal volume MV as compared to WT mice. Third, in WT mice undergoing the LPS/high tidal volume MV, we observed HMGB1 presence in lung lavage fluid. Moreover, MV increased levels of soluble RAGE in lung lavage fluid, with the highest levels found in LPS/high tidal volume-ventilated mice. Administration of soluble RAGE to LPS/high tidal volume-ventilated RAGE KO mice attenuated the production of inflammatory mediators.
  
  
  CONCLUSIONS
  RAGE was not a crucial contributor to the pro-inflammatory state induced by MV. However, the presence of sRAGE limited the production of pro-inflammatory mediators in our 2-hit model of LPS and high tidal volume MV.
authors.affiliation: Laboratory of Experimental Intensive Care and Anesthesiology (L.E.I.C.A), Academic Medical Centre, University of Amsterdam, room M0-220, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands, Ilse.Kuipers@amc.nl.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Kuipers
authors.forename: Hamid
authors.initials: H
authors.lastname: Aslami
authors.forename: Pieter Roel
authors.initials: PR
authors.lastname: Tuinman
authors.forename: Anita M
authors.initials: AM
authors.lastname: Tuip-de Boer
authors.forename: Geartsje
authors.initials: G
authors.lastname: Jongsma
authors.forename: Koenraad F
authors.initials: KF
authors.lastname: van der Sluijs
authors.forename: Goda
authors.initials: G
authors.lastname: Choi
authors.forename: Esther K
authors.initials: EK
authors.lastname: Wolthuis
authors.forename: Joris Jth
authors.initials: JJ
authors.lastname: Roelofs
authors.forename: Paul
authors.initials: P
authors.lastname: Bresser
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Schultz
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.forename: Catharina W
authors.initials: CW
authors.lastname: Wieland