VitA or VitD ameliorates bronchopulmonary dysplasia by regulating the balance between M1 and M2 macrophages

Hong, Zihan; Hu, Hongbo; Rong, Guojie; Huang, Xiuxiu; Tan, Chang; Yu, Xinyuan

doi:10.1016/j.biopha.2021.111836

Cited by 9 publications

(6 citation statements)

References 28 publications

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“…Consistent with previous research, 4 , 9 , 10 this study found that AMs expression increased in BPD mice. Depletion of macrophage partially abolished the EMT process of AECII and alleviated pulmonary differentiation arrest, further supporting that macrophages are regulators of arrested alveolarization in BPD.…”

Section: Discussionsupporting

confidence: 93%

IL‐33‐ST2 pathway regulates AECII transdifferentiation by targeting alveolar macrophage in a bronchopulmonary dysplasia mouse model

Zhu

Yao

Lü

et al. 2022

J Cellular Molecular Medi

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Evidence points to the indispensable function of alveolar macrophages (AMs) in normal lung development and tissue homeostasis. However, the importance of AMs in bronchopulmonary dysplasia (BPD) has not been elucidated. Here, we identified a significant role of abnormal AM proliferation and polarization in alveolar dysplasia during BPD, which is closely related to the activation of the IL‐33‐ST2 pathway. Compared with the control BPD group, AMs depletion partially abolished the epithelialmesenchymal transition process of AECII and alleviated pulmonary differentiation arrest. In addition, IL‐33 or ST2 knockdown has protective effects against lung injury after hyperoxia, which is associated with reduced AM polarization and proliferation. The protective effect disappeared following reconstitution of AMs in injured IL‐33 knockdown mice, and the differentiation of lung epithelium was blocked again. In conclusion, the IL‐33‐ST2 pathway regulates AECII transdifferentiation by targeting AMs proliferation and polarization in BPD, which shows a novel strategy for manipulating the IL‐33–ST2‐AMs axis for the diagnosis and intervention of BPD.

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Section: Discussionsupporting

confidence: 93%

IL‐33‐ST2 pathway regulates AECII transdifferentiation by targeting alveolar macrophage in a bronchopulmonary dysplasia mouse model

Zhu

Yao

Lü

et al. 2022

J Cellular Molecular Medi

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“…EZH2 was shown to be highly expressed in peripheral blood macrophages in a septic state, which was in parallel with our bioinformatics results [ 16 ]. The specific inhibitor of EZH2 can significantly inhibit the M1 differentiation of peritoneal macrophages, thereby reducing the inflammatory response in SALI [ 17 , 18 ]. The expressions of EZH2 in peripheral blood T lymphocytes and B lymphocytes of septic patients were both related to the severity of the disease, and the higher the expression of EZH2, the more severe the disease of septic patients [ 19 , 20 , 21 , 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of EZH2 Ameliorates Sepsis Acute Lung Injury (SALI) and Non-Small-Cell Lung Cancer (NSCLC) Proliferation through the PD-L1 Pathway

Wang

Guo

Wang

et al. 2022

Cells

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(1) Background: Both sepsis acute lung injury (SALI) and non-small-cell lung cancer (NSCLC) are life-threatening diseases caused by immune response disorders and inflammation, but the underlining linking mechanisms are still not clear. This study aimed to detect the shared gene signature and potential molecular process between SALI and NSCLC. (2) Methods: RNA sequences and patient information on sepsis and NSCLC were acquired from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was used to build a co-expression network associated with sepsis and NSCLC. Protein–protein interaction (PPI) analysis of shared genes was intuitively performed by the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The involvement of EZH2 in the tumor immune microenvironment (TIME) and sepsis immune microenvironment (IME) was assessed by R software. Western blot, flow cytometry, and other in vitro assays were performed to further confirm the function and mechanism of EZH2 in NSCLC and SALI. (3) Results: WGCNA recognized three major modules for sepsis and two major modules for NSCLC, and there were seven shared genes identified for the two diseases. Additionally, the hub gene EZH2 was screened out. It was shown that EZH2 was closely related to the IME in the two diseases. In the validation assay, our data showed that EZH2 was expressed at a higher level in peripheral blood mononuclear cells (PBMCs) of septic patients than those of healthy donors (HDs), and EZH2 was also expressed at a higher level in lipopolysaccharide (LPS)-induced PBMCs and non-small cell lung cancer (A549) cells. EZH2 inhibitor (GSK343) downregulated the proliferation ability of A549 cells in a concentration-dependent manner, parallel with the decreased expression level of PD-L1. Similarly, GSK343 inhibited PD-L1 protein expression and downregulated the level of proinflammatory factors in LPS-induced PBMCs. In the co-culture system of PBMCs and human type II alveolar epithelial cells (ATIIs), the addition of GSK343 to PBMCs significantly downregulated the apoptosis of LPS-induced ATIIs. (4) Conclusions: This study illustrated that EZH2 inhibition could ameliorate A549 cell proliferation and LPS-induced ATII apoptosis in parallel with downregulation of PD-L1 protein expression, which provided new insights into molecular signaling networks involved in the pathogenetics of SALI and NSCLC.

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“…6 VitD has been shown to relieve pulmonary injury, inflammation, and apoptosis in a hyperoxia-induced mouse model. 7,8 Finally, preclinical studies of BPD have shown that VitD has potential effects on lung development as it regulates cell growth and apoptosis. 9,10 The mitogen-activated protein kinase (MAPK) pathway involves MEK1/2 and ERK1/2 kinases, which regulate cell proliferation, inflammation, and apoptosis, and activation of the pathway by phosphorylation of key targets is known to play a crucial role in cancer.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Vitamin D Ameliorates Apoptosis and Inflammation by Targeting the Mitochondrial and MEK1/2-ERK1/2 Pathways in Hyperoxia-Induced Bronchopulmonary Dysplasia

Hu¹,

Wu²,

Wang³

et al. 2022

JIR

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Bronchopulmonary dysplasia (BPD) is a common and severe complication in preterm infants. Vitamin D (VitD) has been reported to protect against BPD; however, its role in the mitochondria-mediated and MEK1/2-ERK1/2 pathways has not yet been reported. Methods: We first performed in vivo studies using neonatal C57BL/6 mice in which we induced BPD by exposing them to a hyperoxic environment (85% O 2 ). The mice were divided into room air (RA; 21% O 2 ), RA+VitD, BPD, and BPD+VitD groups. Hematoxylin and eosin and Masson's trichrome staining were used to evaluate lung injury. Inflammation and apoptosis were measured using ELISA, RT-qPCR, and TUNEL assays. We then analyzed BEAS-2B cells divided into the same groups along with an additional BPD+VitD+inhibitor group. Mitochondrial apoptosis was evaluated by transmission electron microscopy, mitochondrial membrane potential, and Western blotting. We then used VDR-shRNA to silence the Vitamin D Receptor (VDR) in the BEAS-2B cells. The inflammation, apoptotic rate, and the phosphorylated forms of MEK1/2 and ERK1/2 in cells were detected by RT-qPCR, flow cytometry, and Western blotting. Results: The mean linear intercept, septal thickness, and abnormal fibrosis increased, while radial alveolar count decreased in BPD lungs compared to RA lungs. VitD administration was able to ameliorate the phenotype in BPD lungs. IL-6, IFN-γ, and TNF-α expression and the apoptotic rate decreased in the BPD+VitD lung group. VitD pretreatment restored abnormal mitochondrial morphology, reduced mitochondrial membrane loss, and reduced the expression of cleaved caspase-3, Bax, and Bcl-2 in BEAS-2B cells. VitD administration also reduced IL-6, IFN-γ, and TNF-α mRNA, as well as pMEK1/2 and pERK1/2 expression and apoptosis rate in cells exposed to hyperoxia. Conclusion:We concluded that VitD treatment ameliorated apoptosis and inflammation by targeting the mitochondrial pathway and via the MEK1/2-ERK1/2 signaling pathway in BPD, thus supporting its potential therapeutic use in this condition.

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VitA or VitD ameliorates bronchopulmonary dysplasia by regulating the balance between M1 and M2 macrophages

Cited by 9 publications

References 28 publications

IL‐33‐ST2 pathway regulates AECII transdifferentiation by targeting alveolar macrophage in a bronchopulmonary dysplasia mouse model

IL‐33‐ST2 pathway regulates AECII transdifferentiation by targeting alveolar macrophage in a bronchopulmonary dysplasia mouse model

Inhibition of EZH2 Ameliorates Sepsis Acute Lung Injury (SALI) and Non-Small-Cell Lung Cancer (NSCLC) Proliferation through the PD-L1 Pathway

Vitamin D Ameliorates Apoptosis and Inflammation by Targeting the Mitochondrial and MEK1/2-ERK1/2 Pathways in Hyperoxia-Induced Bronchopulmonary Dysplasia

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