G6PD is a critical enabler of hypoxia-induced accumulation of macrophages and platelets in mice lungs and contributor to lung inflammation.
Vascul Pharmacol
; 144: 106976, 2022 06.
Article
em En
| MEDLINE
| ID: mdl-35272030
ABSTRACT
Metabolic reprogramming-driven inflammation is emerging as central processes in the pathogenesis of pulmonary hypertension (PH). Although extensive work is ongoing to elucidate the role of inflammation in the remodeling of the pulmonary vasculature, the identity of macrophages and the role of increased glycolysis/glucose-6-phosphate dehydrogenase (G6PD) activity in fueling inflammation in the lung remains unclear. Our objective was to characterize inflammatory cell types in the lungs of hypoxic mice, a model of PH, and to investigate the effects of G6PD on hypoxia-induced accumulation of immunogenic/inflammatory cells in lungs. C57BL/6 mice were exposed to 10% O2. Our results revealed that hypoxia stimulated a time-dependent increase of CD11b+-cells in the bone marrow and blood. In the lung, hypoxia increased genes encoding M2a-macrophage markers. Unexpectedly, we also discovered that CD41+-platelets were the source of TNFα and that their numbers were increased in the lungs of hypoxic mice. Inhibition of G6PD activity with (3ß,5α)-3,21-dihydroxypregnan-20-one suppressed (P < 0.05) expression of genes encoding CD163 and ARG-1 (M2a-macrophage marker) and CD41+TNFα+-platelets in lungs of hypoxic mice. Moreover, there were fewer CD41+TNFα+-platelets in lungs of hypoxic G6PD-deficient mice than their normoxic-controls. Collectively, these results reveal new observations that platelets secreting TNFα combined with macrophages potentially contribute to the pathogenesis of hypoxia-induced PH, and most importantly treatment of hypoxic mice with G6PD activity inhibitor decreased accumulation of the macrophages, platelets, and proinflammatory cytokines, in the lungs. Therefore, G6PD appears to be a good pharmacotherapeutic target to reduce lung inflammation.
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Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
4_TD
Base de dados:
MEDLINE
Assunto principal:
Pneumonia
/
Hipertensão Pulmonar
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Vascul Pharmacol
Ano de publicação:
2022
Tipo de documento:
Article