Skip to main content

Volume 3 Supplement 1

ESICM LIVES 2015

Inhibition of receptor for advanced glycation end-products (RAGE) improves alveolar fluid clearance and lung injury in a mouse model of acute respiratory distress syndrome (ARDS)

Rationale

The receptor for advanced glycation end-products (RAGE) is a transmembrane multipattern receptor abundantly expressed on the basal surface of alveolar type (AT) I cells. RAGE is implicated in ARDS-associated alveolar inflammation [1,2], but its precise roles in lung injury remain unknown. It has been shown recently that RAGE axis could impact alveolar fluid clearance (AFC) through the modulation of epithelial sodium channels [3]. In mouse models of sepsis and of ARDS, treatment with anti-RAGE monoclonal antibody decreased mortality, and treatment with recombinant soluble RAGE (sRAGE, acting as a decoy receptor) was associated with improved lung injury.

Objective

Using a murine model of ARDS, we evaluated whether RAGE modulation could regulate lung injury and AFC.

Methods

60 anesthetised male C57BL/6JTj mice were divided in 4 groups; 3 of them underwent orotracheal installation of hydrochloric acid (day 0). Among these acid-injured mice, some were intravenously treated with an anti-RAGE monoclonal antibody (mAb) or intraperitoneal recombinant soluble RAGE (sRAGE). Mice from the Sham group underwent orotracheal instillation of saline and served as controls. At specified time-points (day 0, 1, 2 and 4), lung injury was assessed after a 30-minute period of mechanical ventilation by analysis of blood gases, alvolar permeability index, bronchoalveolar lavage (BAL) fluid content in interleukin (IL)-6 and AFC. AFC was calculated detecting changes into alveolar protein levels over time.

Results

Acid-injured mice had higher permeability indexes, higher BAL IL-6 and marked hypoxemia on day 1 and 2, as compared with sham animals. AFC rates and PaO2/FiO2 ratios were higher in controls (35%/30min and 281 [262-319], respectively) than in HCl-injured mice on day 1 (8% and 181 [176-198], respectively, P < 0.0001) and day 2 (9% and 186 [174-205], respectively, P < 0.0001).

RAGE inhibition restored AFC on day 1 in both mAb-treated (8% versus 36%, p = 0.009) and sRAGE-treated (8% versus 37% p = 0,009) mice. RAGE inhibition significantly improved both PaO2/FiO2 ratio and permeability index on day 1, day 2, and anti-RAGE therapy could prevent increased BAL IL-6 levels on day 1 an day 2 in HCl-treated mice.

Discussion

Our results support the efficacy of a RAGE inhibition strategy in improving AFC and lung injury in a translational mouse model of ARDS, and RAGE pathway may represent a therapeutic target during ARDS. Such findings should stimulate further research on the mechanistic links between RAGE pathway, AFC and lung alveolar injury and its resolution.

Figure 1
figure 1

Mice lung injury over time.

References

  1. Genes Cells. 2004, 9 (2): 165-74. 10.1111/j.1356-9597.2004.00712.x.

  2. Crit Care Med. 2011, 39 (3): 480-488. 10.1097/CCM.0b013e318206b3ca.

  3. Am J Respir Cell Mol Biol. 2015, 52 (1): 75-87. 10.1165/rcmb.2014-0002OC. Jan

Download references

Author information

Affiliations

Authors

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Blondonnet, R., Audard, J., Clairefond, G. et al. Inhibition of receptor for advanced glycation end-products (RAGE) improves alveolar fluid clearance and lung injury in a mouse model of acute respiratory distress syndrome (ARDS). ICMx 3, A804 (2015). https://doi.org/10.1186/2197-425X-3-S1-A804

Download citation

  • Published:

  • DOI: https://doi.org/10.1186/2197-425X-3-S1-A804

Keywords

  • Lung Injury
  • Sham Group
  • Acute Respiratory Distress Syndrome
  • Alveolar Type
  • Decoy Receptor