Lever les barrières pour résoudre l'inflammation cardiovasculaire avec lipides bioactifs

Keywords

Resolution of inflammation, Specialized proresolving mediators, Drug formulation, Bioavailability, Atherosclerosis, Heart failure

Subject details

Chronic inflammation is increasingly recognized as a major driver of cardiovascular diseases, including atherosclerosis and heart failure, and remains a significant residual risk factor despite current therapies. Although anti-inflammatory interventions have demonstrated clinical benefits, their development has been hampered by adverse effects, notably increased susceptibility to infections due to immunosuppression. These limitations highlight the need for alternative strategies that do not suppress immune competence but instead promote the natural resolution of inflammation. Resolution of inflammation is an active, highly regulated biological process orchestrated by specialized pro-resolving mediators (SPMs), a class of bioactive lipid molecules derived from polyunsaturated fatty acids. These mediators, including resolvins, lipoxins and maresins, act to terminate inflammation, promote tissue repair, and restore homeostasis while preserving host defence mechanisms. Despite strong preclinical evidence supporting their therapeutic potential, their clinical translation remains limited. A major bottleneck is the lack of effective strategies to ensure their stability, bioavailability, and delivery in vivo. This project aims to address these challenges by developing innovative approaches for the formulation and delivery of bioactive lipid mediators, with a particular focus on their transport across biological barriers. Indeed, the gastrointestinal tract and mucosal interfaces represent major obstacles to the successful administration of lipid mediators, due to enzymatic degradation, limited absorption, and physicochemical instability. Improving the bioavailability of these molecules therefore requires the design of suitable drug formulation strategies capable of protecting them and facilitating their transport. To this end, the project will explore advanced lipid-based delivery systems, such as liposomal formulations, to enhance the stability and transport of bioactive mediators. These systems will be characterized physicochemically and evaluated for their ability to cross relevant biological barriers using established in vitro models. Particular attention will be paid to the mechanisms governing barrier permeability and the impact of formulation parameters on transport efficiency. A critical aspect of the project is to determine whether bioactive lipid mediators retain their biological activity following formulation and barrier passage. This will be assessed in well-established cellular models relevant to cardiovascular inflammation. Functional assays will evaluate key mechanisms involved in inflammation resolution, including modulation of inflammatory responses, reactive oxygen species production, and phagocytic and efferocytic clearance of cellular and molecular targets. These analyses will provide essential insights into the relationship between delivery, bioavailability, and biological efficacy. By integrating expertise in cardiovascular pathophysiology, inflammation biology, and drug formulation, this multidisciplinary project aims to bridge a critical gap between fundamental discoveries in inflammation resolution and their therapeutic application. It addresses a key unmet need in the field by focusing not only on the biological activity of bioactive lipids but also on the practical challenges associated with their delivery. In the short to medium term, the project is expected to advance the understanding of the determinants of bioactive lipid bioavailability and barrier transport. In the longer term, it may contribute to the development of innovative therapeutic strategies targeting inflammation resolution, with potential applications in cardiovascular diseases and beyond. More broadly, the outcomes could support the emergence of safer and more physiological approaches to controlling chronic inflammation, with significant societal and biomedical implications.