scholarly journals CircN4bp1 Facilitates Sepsis-Induced Acute Respiratory Distress Syndrome through Mediating Macrophage Polarization via the miR-138-5p/EZH2 Axis

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Dongyang Zhao ◽  
Chunxue Wang ◽  
Xiandong Liu ◽  
Na Liu ◽  
Shougang Zhuang ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Macrophage Activation ◽  
Distress Syndrome ◽  
Rna Binding ◽  
Macrophage Polarization ◽  
Expression Patterns ◽  
Luciferase Reporter ◽  
M1 Macrophage

We recently reported the differential circRNA expression patterns of the pulmonary macrophages in sepsis-induced acute respiratory distress syndrome (ARDS) mice model by microarray analysis. However, their function and hidden molecular mechanism in regulation of macrophage activation and inflammation remain poorly understood. In this study, we found that circN4bp1was overexpressed in PBMC and monocytes, and its expression levels were correlated with a poor prognosis in sepsis induced ARDS patients induced by sepsis. Knockdown of circN4bp1 inhibited the lung injury and improved the long-time survival through blunting the M1 macrophage activation in cecal ligation and puncture- (CLP-) induced ARDS mice. Moreover, bioinformatics analysis predicated a circN4bp1/miR-138-5p ceRNA network, which was confirmed by luciferase reporter assay and RNA binding protein immunoprecipitation (RIP). CircN4bp1 affected macrophage differentiation by binding to miR-138-5p, thus regulating the expression of EZH2 in vivo and ex vivo. Lastly, the m6A level of circN4bp1was found to be elevated in ARDS mice; inhibition of m6A methyltransferase METTL3 blocked this response in vitro. Therefore, circN4bp1 can function as a miR-138-5p sponge for the modulation of macrophage polarization through regulation the expression of EZH2 and may serve as a potential target and/or prognostic marker for ARDS patients following sepsis.

scholarly journals CircN4bp1 Facilitates Sepsis-Induced Acute Respiratory Distress Syndrome Through Mediating Macrophage Polarization via the miR-138-5p/EZH2 Axis

2021 ◽  
Author(s):  
Dongyang Zhao ◽  
Chunxue Wang ◽  
Xiandong Liu ◽  
Na Liu ◽  
Shougang Zhuang ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Rna Binding ◽  
Macrophage Polarization ◽  
Expression Patterns ◽  
Cecal Ligation ◽  
Luciferase Reporter ◽  
Mice Model ◽  
Quantitative Expression ◽  
M1 Macrophage

Abstract Background We recently reported the differential circRNAs expression patterns of the pulmonary macrophages in sepsis induced ARDS mice model by microarray analysis; However, their function and hidden molecular mechanism in regulation of macrophage activation and inflammation remains poorly understood. Methods In this study, serum were obtained from ARDS patients post sepsis and control subjects. Mice were subjected to Cecal ligation and puncture (CLP) surgery and intravenously injected with si-circN4bp1 plasmid transfected macrophages. Raw264.7 cells and MH-S cells were transfected with circN4bp1 overexpression or silence vectors and then polarized as M1 or M2 macrophages in vitro. Results We firstly examined the quantitative expression and localization of circN4bp1 in macrophages by Real-time PCR and fluorescence in situ hybridization (FISH), and found that circN4bp1 was overexpressed in PBMC and monocytes and its expression levels were correlated with a poor prognosis in ARDS patients induced by sepsis. In CLP-induced ARDS mice, we demonstrated that knockdown of circN4bp1 inhibited the lung injury and inflammatory cytokine release, and improved the long-time survival through blunting the M1 macrophage activation. Moreover, bioinformatics analysis predicated a circN4bp1/miR-138-5p ceRNA network, which was confirmed by Luciferase reporter assay and RNA binding protein immunoprecipitation (RIP). In vitro experiments, we indicated that circN4bp1 affected macrophage differentiation by binding to miR-138-5p, thus regulating the expression of EZH2. Lastly, we found that the m6A level of circN4bp1 was elevated in ARDS mice; inhibition of m6A methyltransferases METTL3 blocked this response in vitro. Conclusions These data suggest that circN4bp1 can function as a miR-138-5p sponge for the regulation of macrophage polarization and may serve as a potential target and/or prognostic marker for ARDS patients following sepsis.

scholarly journals Macrophage activation in obese type 2 diabetes: an enhanced risk for COVID-19 and Acute Respiratory Distress Syndrome?

2020 ◽  
Author(s):  
Abu Moin ◽  
Thozhukat Sathyapalan ◽  
Ilhame Diboun ◽  
Stephen Atkin ◽  
Alexandra Butler
Keyword(s):  
Type 2 Diabetes ◽  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Macrophage Activation ◽  
Distress Syndrome ◽  
Serum Glucose ◽  
M2 Macrophage ◽  
Activation Markers ◽  
M1 Macrophage

Abstract Objective Hyperactivation of the immune system through obesity and diabetes may enhance infection severity complicated by Acute Respiratory Distress Syndrome (ARDS), the hallmark of severe COVID-19 disease. Objectives: to determine the circulatory biomarkers for macrophage activation at baseline and after serum glucose normalization in obese type 2 diabetes (OT2D) subjects.Methods A case-controlled interventional pilot study in OT2D (n=23) and control subjects (n=23). Subjects underwent hyperinsulinemic clamp normalizing serum glucose. Plasma macrophage-related proteins were determined using Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement at baseline (control and OT2D subjects) and after 1-hour of insulin clamp (OT2D subjects only).Results. Basal M1 macrophage activation was characterized by elevated levels of M1 macrophage-specific surface proteins, CD80 and CD38, and cytokines or chemokines (CXCL1, CXCL5, RANTES) released by activated M1 macrophages. Two potent M1 macrophage activation markers CXCL9 and CXCL10 were decreased in OT2D. Activated M2 macrophages were characterized by elevated levels of plasma CD163, TFGβ-1, MMP7 and MMP9 in OT2D. Conventional mediators of both M1 and M2 macrophage activation markers (IFN-γ, IL-4, IL-13) were not altered. No changes were observed in plasma levels of M1/M2 macrophage activation markers in OT2D in response to acute normalization of glycemia.Conclusion In the basal state, macrophage activation markers are elevated, and these reflect the expression of circulatory cytokines, chemokines, growth factors and matrix metalloproteinases in obese individuals with type 2 diabetes, that were not changed by glucose normalisation. These differences may predispose the diabetic individuals to ARDS reflecting in increased COVID-19 disease severity.

scholarly journals Silencing of long noncoding RNA H19 alleviates pulmonary injury, inflammation and fibrosis in acute respiratory distress syndrome rats through regulating MicroRNA-423-5p

2020 ◽  
Author(s):  
Xianyu Mu ◽  
Hongrong Wang ◽  
Haiyong Li
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Distress Syndrome ◽  
Luciferase Reporter ◽  
Pulmonary Injury ◽  
Tnf Α ◽  
Histology Score

Abstract Background: This study aimed to explore the function of long noncoding RNA H19 (H19) on pulmonary injury, inflammation and fibrosis in lipoproteins (LPS)-induced acute respiratory distress syndrome (ARDS) rats. Methods: The LPS-induced ARDS rat model was established by intratracheal instillation with 2 mg/kg LPS. QRT-PCR was performed to detect the expression of H19, miR-423-5p, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6,, monocyte chemoattractant protein (MCP)-1 and vascular endothelial growth factor (VEGF). Histology score was detected by hematoxylin-eosin (HE) staining. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of proinflammatory cytokines and the concentration of VEGF in bronchoalveolar lavage fluid (BALF). The protein expression of fiber factors was measured by western blot. The degree of fibrosis was observed by masson-trichrome staining. Dual-luciferase reporter assay was used to determine the binding site between miR-423-5p and H19.Results: The expression of H19 was significantly increased, while miR-423-5p was decreased in LPS-induced ARDS rats. Silencing of H19 decreased the mRNA expression of TNF-α, IL-1β, IL-6, MCP-1 and VEGF in LPS-induced ARDS rats, and decreased the levels of TNF-α, IL-1β, IL-6and the concentration of VEGF in BALF, histology score of LPS-induced ARDS rats. H19 inhibition also decreased the fibrosis score and the proteins expression of fiber factors of LPS-induced ARDS rats. Furthermore, miR-423-5p eliminated the effect of H19 on LPS-induced MH-S cells.Conclusions: Silencing of H19 ameliorated the pulmonary injury, inflammation and fibrosis of LPS-induced ARDS through regulating miR-423-5p, which may be a promising therapeutic strategy to treat ARDS.

Macrophage Polarization Favors Epithelial Repair During Acute Respiratory Distress Syndrome*

2018 ◽  
Vol 46 (7) ◽  
pp. e692-e701 ◽  
Author(s):  
Marc Garnier ◽  
Aude Gibelin ◽  
Arnaud A. Mailleux ◽  
Véronique Leçon ◽  
Margarita Hurtado-Nedelec ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Macrophage Polarization ◽  
Epithelial Repair

scholarly journals The Role of Macrophages in the Pathogenesis of SARS-CoV-2-Associated Acute Respiratory Distress Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Anna Kosyreva ◽  
Dzhuliia Dzhalilova ◽  
Anastasia Lokhonina ◽  
Polina Vishnyakova ◽  
Timur Fatkhudinov
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Macrophage Activation ◽  
Distress Syndrome ◽  
Innate And Adaptive Immunity ◽  
Cell Therapies ◽  
Coronavirus Infection ◽  
Inflammatory Phenotypes

Macrophages are cells that mediate both innate and adaptive immunity reactions, playing a major role in both physiological and pathological processes. Systemic SARS-CoV-2-associated complications include acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation syndrome, edema, and pneumonia. These are predominantly effects of massive macrophage activation that collectively can be defined as macrophage activation syndrome. In this review we focus on the role of macrophages in COVID-19, as pathogenesis of the new coronavirus infection, especially in cases complicated by ARDS, largely depends on macrophage phenotypes and functionalities. We describe participation of monocytes, monocyte-derived and resident lung macrophages in SARS-CoV-2-associated ARDS and discuss possible utility of cell therapies for its treatment, notably the use of reprogrammed macrophages with stable pro- or anti-inflammatory phenotypes.

scholarly journals Identification of a Circulating miRNA Signature to Stratify Acute Respiratory Distress Syndrome Patients

2020 ◽  
Author(s):  
Gennaro Martucci ◽  
Antonio Arcadipane ◽  
Fabio Tuzzolino ◽  
Giovanna Occhipinti ◽  
Giovanna Panarello ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Pilot Study ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Target Genes ◽  
Distress Syndrome ◽  
Expression Patterns ◽  
Hierarchical Cluster ◽  
Blood Levels ◽  
Circulating Microrna

Abstract Background Acute respiratory distress syndrome (ARDS) is a clinical definition of a inflammatory lung disease comprising a heterogeneous group of causes. Despite the fact that veno-venous extracorporeal membrane oxygenation (V-V ECMO) may efficaciously support the most severe cases of ARDS, the mortality is still high. There is a need to improve both ARDS diagnosis and clinical management, particularly with ECMO, and different biomarkers have been tested to implement a precision-focused approach. Methods We included 11 ARDS patients treated with V-V ECMO in a prospective observational pilot study. Clinical baseline, main ECMO management, and outcome-related data were collected. Blood samples were obtained before cannulation, and screened for the expression of 754 circulating microRNA (miRNAs) using high-throughput qPCR. A hierarchical cluster analysis was applied to allow grouping of patients with similar expression patterns. The miRNet database was used to predict target genes of deregulated miRNAs, and the DIANA tool was used to identify significant enrichment pathways, while logistic regression was used to determine the area under the curve (AUC) for associations between miRNA expression and ARDS severity.Results A hierarchical cluster of 229 miRNAs (identified after quality control screening) produced a clear separation of patients into two groups: considering the baseline SAPS II, SOFA and RESP score, cluster A (n=6) showed higher severity compared to cluster B (n=5); all p values<0.05. After analysis of differentially expressed miRNAs between the two clusters, 95 deregulated miRNAs were identified and reduced to 13 by in silico analysis. These miRNAs (miR-93, 92a, -769, -99a, -212, -20a, -19b, -18a, -17, -126, -106b, -19a and let-7a) target genes implicated in tissue remodeling, immune system and blood coagulation pathways; the AUCs were 0.86, 0.90, 0.86, 0.93, 0.90, 0.93, 0.93, 0.88, 0.96, 0.90, 0.80, 0.93 and 0.86, respectively (all p value<0.01).Conclusions This pilot study shows that the blood levels of 13 miRNAs strongly related to biological pathways possibly associated with ARDS are altered in patients with severe ARDS, and may offer diagnostic value as well as contribute to ARDS stratification. Further investigations will have to match miRNA results with inflammatory biomarkers and clinical data to confirm these preliminary observations.

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