Soutenance de thèse Antoine PERSELLO

Equipe

Equipe IIb - Heart failure and pharmacological approaches

Directeur de thèse

Benjamin LAUZIER

Co-directeur de thèse

Bertrand ROZEC

Co-encadrant

Jury

• Paul-Michel MERTES - Professeur des universités – Praticien hospitalier – NHC - Strasbourg (Examinateur)
• Fabienne FOUFELLE - Directeur de recherche INSERM-CRC - Inserm - UMRS 1138 (Examinateur)
• Anne Claire LUKASZEWICZ - Professeur des universités – Praticien hospitalier – Hospices civiles de Lyon (Examinateur)

Résumé

Cardiopulmonary bypass (CPB) is a gold standard procedure in cardiac surgery that aim to replace cardio-pulmonary function. The blood contact with the extrinsic elements of the circuit promotes inflammation leading to a systemic inflammatory response syndrome and homeostasis dysregulation.  The consequences of this deregulation can lead to multi-organ dysfunction. In this context, there is an urgent need to develop new pharmacological approach to reduce the consequences of CPB. Modulation of the ubiquitous stress response pathway (ISR) is a promising approach that has already been proven in other pathologies. ISR activation allows an adapted cellular response for the resolution of stress. The aim of my thesis was to evaluate the therapeutic effect of inhibitors of the GADD34/PP1c phosphatase complex which is responsible for the termination of ISR. To this purpose, a rat model mimicking CPB was developed. The relevance of this model was first validated for preclinical use by hemodynamic and biochemical monitoring and by comparison to parameters found in humans. Finally, we have demonstrated beneficial effects on hemodynamic, pulmonary, renal, and cerebral parameters after administration of the compounds, associated with an anti-inflammatory effect on this model. These effects and the associated mechanisms are currently being under investigation.