Contribution of hypoxia inducible factor, HIF1α, to vascular inflammation and remodeling in giant cell arteritis (GCA). Effects of GM-CSF receptor blockade on HIF1α stabilization
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Medientyp:
E-Book
Titel:
Contribution of hypoxia inducible factor, HIF1α, to vascular inflammation and remodeling in giant cell arteritis (GCA). Effects of GM-CSF receptor blockade on HIF1α stabilization
Erschienen:
[Erscheinungsort nicht ermittelbar]: Universitat de Barcelona, 2022
Sprache:
Englisch
Identifikator:
Entstehung:
Hochschulschrift:
Dissertation, Universitat de Barcelona, 2022
Anmerkungen:
Beschreibung:
Giant Cell Arteritis (GCA) is an immune-mediated disease affecting large and medium sized arteries. Its pathophysiology is not fully understood and its present treatment relies on glucocorticoids, which have important side effects. Therefore, studying the disease and finding new treatments is an unmet medical need. GCA lesions undergo several changes during the development of the disease. Thickening and remodeling of the vascular wall are due to the aberrant inflammatory infiltrate. These changes promote angiogenesis. Angiogenesis is one of the main consequences of hypoxia, through stabilization and induction of Hypoxia Inducible Factor 1 alpha (HIF1α). Several inflammatory molecules such as IL6, IL1β, TNFα and IFNγ, present in GCA lesions, have been demonstrated to be able to stabilize HIF1α. Moreover, several HIF1α target genes like IL6 and other proinflammatory molecules are present in GCA lesions. Moreover, vascular smooth muscle cells (VSMC) are able to express HIF1α under certain conditions. GM-CSF is an important inflammatory mediator expressed by several inflammatory and vascular resident cells. It downstream pathway includes JAK/STAT activation. Regarding GCA, GM-CSF can be affecting several important points of its pathogenesis, from initial dendritic cells activation to leucocyte recruitment and giant cell formation. Considering all these together, our hypothesis for the present thesis is as follows: HIF1⍺ and GM-CSF play an important role in vascular inflammation and remodeling in GCA, through independent or inter-related mechanisms. The objectives are to determine the presence/absence of HIF1α in GCA lesions as well as triggers and consequences of it. To analyze the effect of anti-cytokine targeted therapies in this pathway. To investigate GM-CSF pathway in GCA and the effect of its blockade with mavrilimumab. In the present thesis we demonstrate the presence of hypoxia in the GCA lesions as well as the presence of HIF1α in the media layer of GCA temporal arteries. We validate that VSMC, the cells ...