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Évaluation fonctionnelle et structurale des HDL plasmatiques au cours des états inflammatoires

Abstract : Context: the main function of HDLs is the reverse transport of cholesterol from the tissues back to the liver, thus conferring a cardiovascular protective role. HDL also DISPLAY other endothelioprotective properties, in particular anti-inflammatory, antioxidant, anti-apoptotic, anti-infectious and antithrombotic effects. During certain states of chronic inflammation, such as atherosclerosis, changes in HDL function and structure have been previously described, which can have negative consequences on morbidity and mortality. The objective of this thesis was to investigate the structural and concentration changes occurring in human sepsis a model of exacerbated acute inflammation. In addition, we tested the effects of injecting human reconstituted HDLs in several experimental sepsis models. Results: first part, by comparing two exacerbated inflammatory conditions, we showed that the plasma HDL concentration was drastically decreased in patients at the acute phase of sepsis while it was not modified in polytrauma patients. A second part focused on comparing patients in septic shock and non-septic ICU patients. We confirmed these differences in HDL concentration. In addition, septic patients had more large HDL particles compared to control patients who had more small functional particles. A kinetic study of HDL concentration in 205 septic ICU patients showed a drastic decrease at the acute phase and then an increase at patient's recovery without returning to the basal concentrations observed before the hospitalization. HDL concentration was associated with certain morbidity criteria (SOFA score, days alive without mechanical ventilation), but no link to mortality was found in this work. A proteomic analysis of plasma from septic patients found a drastic decrease in many apolipoproteins compared to plasma from non-septic patients. Finally, the injection of human reconstituted HDLs in three mouse models of sepsis showed a decrease in mortality, as well as a decrease in many markers of inflammation and bacterial concentrations in both plasma and tissues. Conclusion: during sepsis, there are both quantitative and qualitative modifications of HDLs with a significant decrease in their concentrations, but also increased particle size and changes in the composition of these particles. The quantitative aspect alone does not seem sufficient to predict patient outcomes; evaluation of HDL dysfunction could represent a better biomarker. In addition, injection of functional HDL has proven its effectiveness in several mouce models. Further studies to characterize these dysfunctions are needed before completing a randomized trial evaluating therapeutic injection of HDL during sepsis in patients.
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Submitted on : Thursday, February 13, 2020 - 1:52:08 PM
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Sébastien Tanaka. Évaluation fonctionnelle et structurale des HDL plasmatiques au cours des états inflammatoires. Médecine humaine et pathologie. Université de la Réunion, 2019. Français. ⟨NNT : 2019LARE0032⟩. ⟨tel-02477471⟩

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