Novel therapeutic approaches to treat inflammatory conditions with glucocorticoid and calciferol nanoparticles in vivo and in vitro
by Agathe Amouret
Date of Examination:2022-10-27
Date of issue:2023-01-10
Advisor:Prof. Dr. Holger Reichardt
Referee:Prof. Dr. Lutz Walter
Referee:Prof. Dr. Francesca Odoardi
Referee:Prof. Dr. Carsten Lüder
Referee:Prof. Dr. Ralf Dressel
Referee:Prof. Dr. Thomas Meyer
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Description:Dissertation Amouret Agathe
Abstract
English
The body is constantly confronted with environmental threats and sometimes the entry of pathogens leads to severe inflammatory conditions such as sepsis or acute lung injury (ALI). Both diseases are characterized by a dysregulated immune system, which compromises homeostasis and induces multiple organ failure, thus being potentially lethal. While pathophysiological changes in ALI are mostly confined to the lung, sepsis is an example of a systemic inflammation affecting different organs including spleen, liver and lung. GCs are used in both conditionsto reduce the so called “cytokine storm”, but high doses of GCs may also aggravate lymphocytopenia occurring in both diseases, leading to a severe risk of secondary infections and poorer outcome. Targeting specific cell types in GC treatment could allow to overcome this side effect as nanoparticles were shown to be mainly taken up by macrophages. Our results revealed that free synthetic GCs and GC-containing nanoparticles efficiently reduced the pro-inflammatory profile and tissue damage in a mouse model of sepsis. However, in contrast to free GCs, a tendency was observed that using nanoparticles prevented a further aggravation of lymphocytopenia. Nonetheless, the therapeutic efficacy of both GC formulations was similar in sepsis as well as ALI mouse models. Interestingly, the analysis of human peripheral blood monocytes also unveiled a novel function of GCs in regulating the energy metabolism of myeloid cells in inflammatory conditions. Finally, nanoparticles containing calcitriol, the active form of vitamin D, were characterized as a potential alternative to GCs in sepsis or ALI therapy allowing to avoid side-effects of high doses of calcitriol. Our results show a good anti- inflammatory effect of newly formulated calcitriol nanoparticles, which were efficiently engulfed by macrophages and fibroblasts in a clathrin-dependent manner before being localized to the lysosomal compartment. Collectively, the use of nanoparticles offers interesting new possibilities for the treatment of inflammatory conditions with the potential to reduce adverse effects of GCs and calcitriol.
Keywords: Sepsis; Acute Lung Injury (ALI); Glucocorticoids; Calciferol; Nanoparticles
Schlagwörter: Sepsis; Acute Lung Injury (ALI); Nanoparticles; Glucocorticoids; Calciferol