The receptor for advanced glycation end products in ventilator-induced lung injury

Kuipers, M. T., Aslami, H., Tuinman, P. R., Tuip-de Boer, A. M., Jongsma, G., van der Sluijs, K. F., Choi, G., Wolthuis, E. K., Roelofs, J. J., Bresser, P., Schultz, M. J., van der Poll, T. & Wieland, C. W., 2-Aug-2014, In : Intensive Care Medicine. 2, 22, 13 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Maria T Kuipers
  • Hamid Aslami
  • Pieter Roel Tuinman
  • Anita M Tuip-de Boer
  • Geartsje Jongsma
  • Koenraad F van der Sluijs
  • Goda Choi
  • Esther K Wolthuis
  • Joris Jth Roelofs
  • Paul Bresser
  • Marcus J Schultz
  • Tom van der Poll
  • Catharina W Wieland

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.

Original languageEnglish
Number of pages13
JournalIntensive Care Medicine
Issue number22
Publication statusPublished - 2-Aug-2014

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