Dataset Information

Glycolytic Reprogramming in Silica-Induced Lung Macrophages and Silicosis Reversed by Ac-SDKP Treatment.

ABSTRACT: Glycolytic reprogramming is an important metabolic feature in the development of pulmonary fibrosis. However, the specific mechanism of glycolysis in silicosis is still not clear. In this study, silicotic models and silica-induced macrophage were used to elucidate the mechanism of glycolysis induced by silica. Expression levels of the key enzymes in glycolysis and macrophage activation indicators were analyzed by Western blot, qRT-PCR, IHC, and IF analyses, and by using a lactate assay kit. We found that silica promotes the expression of the key glycolysis enzymes HK2, PKM2, LDHA, and macrophage activation factors iNOS, TNF-α, Arg-1, IL-10, and MCP1 in silicotic rats and silica-induced NR8383 macrophages. The enhancement of glycolysis and macrophage activation induced by silica was reduced by Ac-SDKP or siRNA-Ldha treatment. This study suggests that Ac-SDKP treatment can inhibit glycolytic reprogramming in silica-induced lung macrophages and silicosis.

SUBMITTER: Mao N

PROVIDER: S-EPMC8465686 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Glycolytic Reprogramming in Silica-Induced Lung Macrophages and Silicosis Reversed by Ac-SDKP Treatment.

Mao Na N Yang Honghao H Yin Jie J Li Yaqian Y Jin Fuyu F Li Tian T Yang Xinyu X Sun Ying Y Liu Heliang H Xu Hong H Yang Fang F

International journal of molecular sciences 20210917 18

Glycolytic reprogramming is an important metabolic feature in the development of pulmonary fibrosis. However, the specific mechanism of glycolysis in silicosis is still not clear. In this study, silicotic models and silica-induced macrophage were used to elucidate the mechanism of glycolysis induced by silica. Expression levels of the key enzymes in glycolysis and macrophage activation indicators were analyzed by Western blot, qRT-PCR, IHC, and IF analyses, and by using a lactate assay kit. We f ...[more]

PMID: 34576239

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Project description:BackgroundAdvances in radiotherapy for thoracic cancers have resulted in improvement of survival. However, radiation exposure to the heart can induce cardiotoxicity. No therapy is currently available to inhibit these untoward effects. We examined whether a small tetrapeptide, N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP), can counteract radiation-induced cardiotoxicity by inhibiting macrophage-dependent inflammatory and fibrotic pathways.Methods and resultsAfter characterizing a rat model of cardiac irradiation with magnetic resonance imaging protocols, we examined the effects of Ac-SDKP in radiation-induced cardiomyopathy. We treated rats with Ac-SDKP for 18 weeks. We then compared myocardial contractile function and extracellular matrix by cardiac magnetic resonance imaging and the extent of inflammation, fibrosis, and Mac-2 (galectin-3) release by tissue analyses. Because Mac-2 is a crucial macrophage-derived mediator of fibrosis, we performed studies to determine Mac-2 synthesis by macrophages in response to radiation, and change in profibrotic responses by Mac-2 gene depleted cardiac fibroblasts after radiation. Cardiac irradiation diminished myocardial contractile velocities and enhanced extracellular matrix deposition. This was accompanied by macrophage infiltration, fibrosis, cardiomyocyte apoptosis, and cardiac Mac-2 expression. Ac-SDKP strongly inhibited these detrimental effects. Ac-SDKP migrated into the perinuclear cytoplasm of the macrophages and inhibited radiation-induced Mac-2 release. Cardiac fibroblasts lacking the Mac-2 gene showed reduced transforming growth factor β1, collagen I, and collagen III expression after radiation exposure.ConclusionsOur study identifies novel cardioprotective effects of Ac-SDKP in a model of cardiac irradiation. These protective effects are exerted by inhibiting inflammation, fibrosis, and reducing macrophage activation. This study shows a therapeutic potential of this endogenously released peptide to counteract radiation-induced cardiomyopathy.

Project description:Cancer survivors treated with thoracic ionizing radiation are at higher risk of premature death due to myocardial ischemia. No therapy is currently available to prevent or mitigate these effects. We tested the hypothesis that an endogenous tetrapeptide N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) counteracts radiation-induced coronary vascular fibrosis and endothelial cell loss and preserves myocardial blood flow. We examined a rat model with external-beam-radiation exposure to the cardiac silhouette. We treated a subgroup of irradiated rats with subcutaneous Ac-SDKP for 18-weeks. We performed cardiac MRI with Gadolinium contrast to examine resting myocardial blood flow content. Upon sacrifice, we examined coronary endothelial-cell-density, fibrosis, apoptosis and endothelial tight-junction proteins (TJP). In vitro, we examined Ac-SDKP uptake by the endothelial cells and tested its effects on radiation-induced reactive oxygen species (ROS) generation. In vivo, we injected labeled Ac-SDKP intravenously and examined its endothelial localization after 4-h. We found that radiation exposure led to reduced resting myocardial blood flow content. There was concomitant endothelial cell loss and coronary fibrosis. Smaller vessels and capillaries showed more severe changes than larger vessels. Real-time PCR and confocal microscopy showed radiation-induced loss of TJ proteins including-claudin-1 and junctional adhesion molecule-2 (JAM-2). Ac-SDKP normalized myocardial blood flow content, inhibited endothelial cell loss, reduced coronary fibrosis and restored TJ-assembly. In vitro, Ac-SDKP localized to endothelial cells and inhibited radiation-induced endothelial ROS generation. In vivo, labeled Ac-SDKP was visualized into the endothelium 4-h after the intravenous injection. We concluded that Ac-SDKP has protective effects against radiation-induced reduction of myocardial blood flow. Such protective effects are likely mediated by neutralization of ROS-mediated injury, preservation of endothelial integrity and inhibition of fibrosis. This demonstrates a strong therapeutic potential of Ac-SDKP to counteract radiotherapy-induced coronary disease.

Dataset Information

Glycolytic Reprogramming in Silica-Induced Lung Macrophages and Silicosis Reversed by Ac-SDKP Treatment.

Publications

Glycolytic Reprogramming in Silica-Induced Lung Macrophages and Silicosis Reversed by Ac-SDKP Treatment.

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