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MIF/CD74 : une nouvelle cible thérapeutique pour l’Hypertension Artérielle Pulmonaire (HTAP)

Abstract : Pulmonary arterial hypertension (PAH) is a severe progressive cardiopulmonary disorder characterized by vascular proliferation and remodeling of the small pulmonary arteries. These can lead to a progressive increase in pulmonary vascular resistance and ultimately to right ventricular failure and death. Pulmonary endothelial dysfunction and pro-inflammatory phenotype associated with PAH are now considered as a key pathogenic mechanism that could be detrimental to both the susceptibility and development of the pulmonary vascular remodeling.In pulmonary endothelial cells (EC), the binding of the immune mediator MIF (Macrophage Migration Inhibitory Factor), to its receptor CD74 initiates an intracellular signaling cascade leading to cell proliferation, cell survival and the secretion of various inflammatory mediators. Therefore, the present work seeks to: (1) Determine the importance of the MIF/CD74 signaling pathway in the acquisition of an abnormal pro-inflammatory EC phenotype in PAH; (2) Test the efficacies of MIF inhibitors, synthesized and patented by MIFCARE, on this abnormal pro-inflammatory EC phenotype and on the development of experimental pulmonary hypertension (PH).Our data highlight the critical role of the MIF/CD74 axis in the endothelial dysfunction and pro-inflammatory phenotype of pulmonary EC in PAH. In addition, our data emphasize its importance as a promising new therapeutic target to prevent the pulmonary vascular remodeling associated to this disorder. Furthermore, we were successful in identifying an agent from a novel class of MIF antagonists optimized for in vivo use that have the ability to partially reverse established PH in rats and to partially inhibit the pro-inflammatory EC phenotype observed in PAH.Collectively, we demonstrated the importance of the MIF/CD74 axis and that its inhibition with MIF antagonist agents could represent a promising strategy for the treatment of PAH (under patent). However, further studies are still needed before transferring this knowledge to clinical use of these new candidates.
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Submitted on : Monday, January 1, 2018 - 1:05:09 AM
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Morane Le Hiress. MIF/CD74 : une nouvelle cible thérapeutique pour l’Hypertension Artérielle Pulmonaire (HTAP). Pneumologie et système respiratoire. Université Paris Sud - Paris XI, 2015. Français. ⟨NNT : 2015PA114828⟩. ⟨tel-01673789⟩

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