Inhibition of the Receptor for Advanced Glycation End-Products in Acute Respiratory Distress Syndrome: A Randomised Laboratory Trial in Piglets
| Autor: | Jules Audard, Loïc Blanchon, Christelle Gross, Vincent Sapin, Thomas Godet, Bertille Paquette, Matthieu Jabaudon, Justine Pasteur, Damien Bouvier, Raiko Blondonnet, Corinne Belville, Jean-Baptiste Joffredo, Marilyne Lavergne, Bruno Pereira, Jean-Michel Constantin |
|---|---|
| Přispěvatelé: | BLANCHON, LOIC, CHU Clermont-Ferrand, Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
ARDS Swine Receptor for Advanced Glycation End Products lcsh:Medicine Pharmacology Gastroenterology [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract RAGE (receptor) Pathogenesis 0302 clinical medicine Interquartile range Glycation MESH: Animals 050207 economics Receptor lcsh:Science MESH: Swine 0303 health sciences Respiratory Distress Syndrome 050208 finance Multidisciplinary 05 social sciences respiratory system 3. Good health medicine.anatomical_structure medicine.symptom MESH: Oxygen medicine.medical_specialty MESH: Hemodynamics Inflammation Lung injury Article 03 medical and health sciences Internal medicine 0502 economics and business medicine Animals 030304 developmental biology Lung business.industry MESH: Receptor for Advanced Glycation End Products lcsh:R Antagonist Hemodynamics Oxygenation Translational research medicine.disease Oxygen Disease Models Animal 030104 developmental biology 030228 respiratory system Preclinical research [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract MESH: Respiratory Distress Syndrome Adult lcsh:Q MESH: Disease Models Animal business 030217 neurology & neurosurgery |
| Zdroj: | Scientific Reports Scientific Reports, 2019, 9 (1), pp.9227. ⟨10.1038/s41598-019-45798-5⟩ Scientific Reports, Nature Publishing Group, 2019, 9 (1), pp.9227. ⟨10.1038/s41598-019-45798-5⟩ Scientific Reports, Vol 9, Iss 1, Pp 1-9 (2019) |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-019-45798-5⟩ |
| Popis: | BackgroundThe receptor for advanced glycation end products (RAGE) modulates the pathogenesis of acute respiratory distress syndrome (ARDS). RAGE inhibition was recently associated with attenuated lung injury and restored alveolar fluid clearance (AFC) in a mouse model of ARDS. However, clinical translation will first require assessment of this strategy in larger animals.MethodsForty-eight anaesthetised Landrace piglets were randomised into a control group and three treatment groups. Animals allocated to treatment groups underwent orotracheal instillation of hydrochloric acid i) alone; ii) in combination with intravenous administration of a RAGE antagonist peptide (RAP), a S100P-derived peptide that prevents activation of RAGE by its ligands, or iii) in combination with intravenous administration of recombinant soluble (s)RAGE that acted as a decoy receptor. The primary outcome measure was net AFC at 4 h. Arterial oxygenation was assessed hourly for 4 h and alveolar-capillary permeability, alveolar inflammation, lung histology and lung mRNA expression of the epithelial sodium channel (α1-ENaC), α1-Na,K-ATPase and aquaporin (AQP)-5 were assessed at 4 h.FindingsTreatment with either RAP or sRAGE improved net AFC rates (median [interquartile range], 21.2 [18.8–21.7] and 19.5 [17.1–21.5] %/h, respectively, versus 12.6 [3.2–18.8] %/h in injured, untreated controls), improved oxygenation and decreased alveolar inflammation and histological evidence of tissue injury after acid-induced ARDS. RAGE inhibition also restored lung mRNA expression of α1-Na,K-ATPase and AQP-5.InterpretationRAGE inhibition restored AFC and attenuated lung injury in a piglet model of acid-induced ARDS.FundingAuvergne Regional Council, Agence Nationale de la Recherche, Direction Générale de l’Offre de Soins.Research in ContextEvidence before this studyThe acute respiratory distress syndrome (ARDS), a clinical syndrome of diffuse pulmonary oedema and inflammation, currently lacks effective therapies and is associated with high mortality and morbidity. The degrees of lung epithelial injury and of alveolar fluid clearance (AFC) impairment, as evaluated by plasma levels of soluble receptor for glycation end-products (RAGE), are major prognostic factors in ARDS and potential therapeutic targets for ongoing research. For example, targeting RAGE with recombinant sRAGE or an anti-RAGE monoclonal antibody has proven beneficial in a translational mouse model of acid-induced ARDS.Added value of this studyIn a piglet model of acid-induced ARDS, treatment with RAGE antagonist peptide or recombinant sRAGE restored AFC and attenuated the features of lung injury, thereby confirming, in the closest evolutionary model species to humans, previous evidence from rodent models that modulation of RAGE may be a therapeutic option for ARDS. Although this is an important step towards future clinical translation, future studies should assess the best methods to modulate RAGE and further confirm the safety of manipulating this pathway in patients with ARDS. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|