Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Clinical Investigation Année : 2008

Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease

Nathalie Sabaa
  • Fonction : Auteur
Lucia De Franceschi
  • Fonction : Auteur
Philippe Bonnin
Yves Castier
  • Fonction : Auteur
Giorgio Malpeli
  • Fonction : Auteur
Haythem Debbabi
  • Fonction : Auteur
Ariane Galaup
  • Fonction : Auteur
Micheline Maier-Redelsperger
  • Fonction : Auteur
Sophie Vandermeersch
  • Fonction : Auteur
Aldo Scarpa
  • Fonction : Auteur
Anne Janin
  • Fonction : Auteur
Bernard Levy
  • Fonction : Auteur
Robert Girot
  • Fonction : Auteur
Yves Beuzard
  • Fonction : Auteur
Christophe Leboeuf
Annie Henri
  • Fonction : Auteur
Jean-Claude Dussaule
  • Fonction : Auteur
Pierre-Louis Tharaux

Résumé

Patients with sickle-cell disease (SCD) suffer from tissue damage and life-threatening complications caused by vasoocclusive crisis (VOC). Endothelin receptors (ETRs) are mediators of one of the most potent vasoconstrictor pathways in mammals, but the relationship between vasoconstriction and VOC is not well understood. We report here that pharmacological inhibition of ETRs prevented hypoxia-induced acute VOC and organ damage in a mouse model of SCD. An in vivo ultrasonographic study of renal hemodynamics showed a substantial increase in endothelin-mediated vascular resistance during hypoxia/reoxygenation-induced VOC. This increase was reversed by administration of the dual ETR antagonist (ETRA) bosentan, which had pleiotropic beneficial effects in vivo. It prevented renal and pulmonary microvascular congestion, systemic inflammation, dense rbc formation, and infiltration of activated neutrophils into tissues with subsequent nitrative stress. Bosentan also prevented death of sickle-cell mice exposed to a severe hypoxic challenge. These findings in mice suggest that ETRA could be a potential new therapy for SCD, as it may prevent acute VOC and limit organ damage in sickle-cell patients.

Dates et versions

hal-02142776 , version 1 (28-05-2019)

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Citer

Nathalie Sabaa, Lucia De Franceschi, Philippe Bonnin, Yves Castier, Giorgio Malpeli, et al.. Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease. Journal of Clinical Investigation, 2008, 118 (5), pp.1924--1933. ⟨10.1172/JCI33308⟩. ⟨hal-02142776⟩
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