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Effet de l'hypoxie sur le développement, la persistance et l'évolution fibrosante des granulomes pulmonaires

Abstract : Sarcoidosis is a systemic granulomatosis of unknown etiology, preferentially affecting the lung.Granuloma formation is thought to be due to a disproportionate immune response to unknownantigen(s) in a genetically predisposed individual. The evolution of the granuloma is variable,ranging from spontaneous resolution to evolution towards fibrosis with still quite unknownmechanisms. Due to the lack of vascularization in the center of granulomas observed inpulmonary biopsies, the macrophages constituting these structures are most likely hypoxic. Wehypothesize that a hypoxic microenvironment could favor the maintenance of the granulomaand its evolution towards fibrosis during sarcoidosis.Firstly, we analyzed the effect of hypoxia (FiO2: 1.5% for 24 hours) in vitro on human bloodmonocyte-derived macrophages (hMDM) from patients with active or inactive pulmonarysarcoidosis and from healthy controls. Hypoxia increased more significantly in activesarcoidosis the activity of HIF-1α, the pro-inflammatory response (TNFα, IL1ß, IL8), withoutNF-kB activation (p65, p50) and the pro-fibrotic response with PAI-1 secretion associated withinhibition of human lung fibroblast migration. These findings were associated with the presenceof HIF-1α and PAI-1 on immunohistochemistry analysis of lung granulomas biopsies. Hypoxiadecreased phagocytosis and CD36 scavenger receptor expression in controls but not insarcoidosis patients. Hypoxia also decreased the expression of CD80/CD86 co-stimulatorymolecules and HLA-DR in active forms of sarcoidosis.Secondly, we studied the effect of prolonged hypoxia (Hx) (15 days) in two in vivo models ofmurine (C57BL/6J) pulmonary granulomatosis induced by carbon nanotubes (NT) andPropionibacterium acnes (PA).In the NT group exposed to hypoxia more granulomas were observed than in the NT groupexposed to normoxia. In contrast, the PA group exposed to hypoxia showed a trend towardfewer granulomas compared with the PA group exposed to normoxia. Il18, Il12b and TnfamRNAs in the NT/Hypoxia group were increased compared to the other groups (p<0.05).Hypoxia decreased Ccl4 and Cxcl9 expression in PA mice (p<0.05). In both models, mice underhypoxia showed fibrosis lesions. Double exposure NT/Hx increased Pdgfb expression,compared with NT/Nx mice (p<0.05) and PBS/Nx mice (p<0.01). Finally, HIF-1 α expressionwas also detected within the granulomas in both models exposed to hypoxia.The response to hypoxia of macrophages from patients with pulmonary sarcoidosis, inparticular the active forms, is characterized by a pro-inflammatory response, a pro-fibrosisresponse, a pro-angiogenic response and a more important phagocytic activity than controls orpatients with a less active disease. Depending on the antigen used to induce pulmonarygranulomatosis in mouse models, hypoxia seems to modulate pulmonary granuloma formationand fibrosis by inducing or inhibiting the expression of cytokines involved in the recruitmentof inflammatory cells. Hypoxia could be a factor favoring the maintenance of granuloma andits evolution towards fibrosis
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Submitted on : Friday, June 17, 2022 - 1:02:51 AM
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Florence Jeny. Effet de l'hypoxie sur le développement, la persistance et l'évolution fibrosante des granulomes pulmonaires. Biologie cellulaire. Université Paris-Nord - Paris XIII, 2021. Français. ⟨NNT : 2021PA131041⟩. ⟨tel-03697500⟩



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