Abstract
Glycolysis and ER stress have been considered important drivers of pulmonary fibrosis. However, it is not clear whether glycolysis and ER stress are interconnected and if those interconnections regulate the development of pulmonary fibrosis. Our previous studies found that the expression of LDHA, a key enzyme involved in glycolysis, was increased in silica-induced macrophages and silicotic models, and it was closely related to silicosis fibrosis by participating in inflammatory response. However, whether pharmacological inhibition of LDHA is beneficial to the amelioration of silicosis fibrosis remains unclear. In this study, we investigated the effects of oxamate, a potent inhibitor of LDHA, on the regulation of glycolysis and ER stress in alveolar macrophages and silicotic mice. We found that silica induced the upregulation of glycolysis and the expression of key enzymes directly involved in ER stress in NR8383 macrophages. However, treatment of the macrophages and silicotic mice with oxamate attenuated glycolysis and ER stress by inhibiting LDHA, causing a decrease in the production of lactate. Therefore, oxamate demonstrated an anti-fibrotic role by reducing glycolysis and ER stress in silicotic mice.
Highlights
Silicosis is an occupational pneumoconiosis caused by the inhalation of free crystalline silicon dioxide (SiO2) or silica dust [1]
We previously demonstrated that the levels of key glycolytic enzymes, including hexokinase2 (HK2), pyruvate kinase M2 (PKM2), lactate dehydrogenase A (LDHA), and the lactate concentration were enhanced in silica-induced alveolar macrophage and silicotic models, suggesting that the metabolic switch to glycolysis is an important driving force for the development of silicosis fibrosis [4]
We examined the effects of oxamate on the regulation of glycolysis and Endoplasmic reticulum (ER) stress in macrophages and a silicotic mouse model and used these data to elucidate the therapeutic mechanism of oxamate in the treatment of silicosis fibrosis
Summary
Silicosis is an occupational pneumoconiosis caused by the inhalation of free crystalline silicon dioxide (SiO2) or silica dust [1]. When macrophages phagocytize silica particles, they must quickly adapt their metabolism to provide sufficient energy to maintain their immunomodulatory functions, including phagocytosis and the production of inflammatory cytokines and chemokines [2]. This metabolic switch from oxidative phosphorylation to glycolytic metabolism provides an energy source for sustaining inflammatory damage [3]. We previously demonstrated that the levels of key glycolytic enzymes, including hexokinase (HK2), pyruvate kinase M2 (PKM2), lactate dehydrogenase A (LDHA), and the lactate concentration were enhanced in silica-induced alveolar macrophage and silicotic models, suggesting that the metabolic switch to glycolysis is an important driving force for the development of silicosis fibrosis [4]. Whether silica exposure increases glycolysis and ER stress in macrophages remains unclear
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