scholarly journals miR-146b-3p regulates PI3K/AKT signaling pathway in septic mice with acute respiratory distress syndrome

2020 ◽  
Author(s):  
Yao Liu ◽  
Jinqiang Zhu ◽  
Xiaohong Jin ◽  
Meiping Dong ◽  
Junfen Zheng
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Signaling Pathway ◽  
Distress Syndrome ◽  
Akt Signaling ◽  
Normal Group ◽  
Akt Signaling Pathway ◽  
Model Group ◽  
Caspase 1

Abstract Background: This study aimed to explore the effect of miR-146b-3p on acute respiratory distress syndrome in septic mice by regulating PI3K/AKT signaling pathway. Methods: Seventy C57BL/6 mice were divided into normal group ( n = 10) and modeling group ( n = 60, mice for constructing septic mice models with acute respiratory distress syndrome). Model mice were subdivided into model group (without any treatment), negative control (NC) mimic group (injection with miRNA NC), miR-146b-3p mimic group (injection with miR-146b-3p mimic), si-NC group (injection with PI3Kγ siRNA NC), si-PI3Kγ group (injection with PI3Kγ interference sequence), and miR-146b-3p mimic + oe-PI3Kγ group (injection with miR-146b-3p mimic + PI3Kγ overexpression plasmid). Dual-luciferase reporter assay was conducted to determine the target relationship between miR-146b-3p and PI3Kγ. Wet weight/dry weight (W/D) ratio of the left lung was measured. Hematoxylin and eosin stain was used to detect the pathological change of mouse lung. ELISA was employed to measure serum interleukin (IL) -1β and IL-18 levels. miR-146b-3p and PI3Kγ expressions were detected by qRT-PCR. PI3Kγ, AKT, NLRP3, apoptosis-associated speck-like protein caspase recruitment domain (ASC) and Caspase-1 protein expressions were detected by Western blotting. Results: miR-146b-3p negatively regulated PI3Kγ. The lung tissues in other groups compared with normal group had down-regulated miR-146b-3p, up-regulated PI3Kγ, p-AKT, ASC, NLRP3 and Caspase-1 proteins, higher W/D ratio, and more serum IL-1β and IL-18 (all P < 0.05). All indicators in miR-146b-3p mimic group and si-PI3Kγ group were significantly improved as compared to model group (all P < 0.05). Up-regulated PI3Kγ, p-AKT, ASC, NLRP3 and Caspase-1 proteins and higher W/D ratio and IL-1β and IL-18 levels in serum existed in miR-146b-3p mimic + oe-PI3Kγ group compared with miR-146b-3p mimic group (all P < 0.05). Conclusions: Up-regulation of miR-146b-3p can restrain PI3K/AKT signaling pathway, thereby improving acute respiratory distress syndrome in septic mice.

scholarly journals Interleukin-1RA Mitigates SARS-CoV-2–Induced Inflammatory Lung Vascular Leakage and Mortality in Humanized K18-hACE-2 Mice

2021 ◽  
Author(s):  
Shiqin Xiong ◽  
Lianghui Zhang ◽  
Justin M. Richner ◽  
Jake Class ◽  
Jalees Rehman ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Failure ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Vascular Injury ◽  
Distress Syndrome ◽  
Lung Edema ◽  
Edema Formation ◽  
Caspase 1 ◽  
Junction Protein

Objective: SARS-CoV-2 infection is a major cause of morbidity and mortality, often as a result of acute respiratory distress syndrome. Respiratory failure is characterized by a hyperinflammatory immune response, lung vascular injury, and edema formation. The potential for immunomodulatory therapy to prevent lung vascular injury and edema formation is not well understood. Approach and Results: We show that SARS-CoV-2 infection in humanized K18-hACE-2 mice activated inflammatory NLRP3–caspase-1 pyroptotic signaling in lungs, release of IL (interleukin)-1β, and downregulation of the lung endothelial adherens junction protein VE-cadherin. Primary human lung microvascular endothelial cells were susceptible to SARS-CoV-2 infection and displayed pyroptosis-like injury. We observed profound lung vascular injury post–SARS-CoV-2 infection and resultant protein-rich lung edema formation. Selective blockade of IL-1 receptor signaling by IL-1RA (IL-1 receptor antagonist) anakinra prevented downregulation of VE-cadherin, as well as accompanying lung vascular hyperpermeability. IL-1RA also significantly increased survival. Conclusions: These results provide insights into the central role of NLRP3–caspase-1 pyroptotic innate immune signaling and loss of lung endothelial adherens junctions in the mechanism of acute respiratory distress syndrome induced by SARS-CoV-2. Our data show that treatment with IL-1RA during activation of inflammasome provides the ideal scenario for preventing lung vascular injury and respiratory failure in coronavirus disease 2019 (COVID-19).

scholarly journals Identification of Key Pathways and Genes of Acute Respiratory Distress Syndrome Specific Neutrophil Phenotype

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Dong Wang ◽  
Yajuan Li ◽  
Changping Gu ◽  
Mengjie Liu ◽  
Yuelan Wang
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Signaling Pathway ◽  
Distress Syndrome ◽  
Neutrophil Activation ◽  
Polymorphonuclear Neutrophil ◽  
Venn Diagram ◽  
Pathway Enrichment Analysis ◽  
Key Pathways

Despite over 50 years of clinical and basic studies, acute respiratory distress syndrome (ARDS) is still a critical challenge with high mortality worldwide. The severity of neutrophil activation was associated with disease severity. However, the detailed pathophysiology of the circulating polymorphonuclear neutrophil activation in ARDS remains unclear. To identify key pathways and genes in the ARDS-specific neutrophil phenotype distinct from sepsis, the datasets of blood polymorphonuclear neutrophils (PMNs) from patients with ARDS (GSE76293) and from sepsis patients (GSE49757) were chosen from the Gene Expression Omnibus (GEO) and analyzed using bioinformatics methods. A total of 220 differential expressed genes (DEGs) were overlapped between GSE49757 and GSE76293 in a Venn diagram. Pathway enrichment analysis results showed that DEGs in GSE76293 were mainly enriched in the MAPK signaling pathway, FoxO signaling pathway, and AMPK signaling pathway relative to GSE49757. We identified 30 hub genes in the protein-protein interaction network. By comparing with GSE49757, we speculated that GAPDH, MAPK8, PIK3CB, and MMP9 may play important roles in the progression of ARDS-specific circulating neutrophil activation. The findings may provide novel insights into the development of promising targets for the diagnosis and treatment of ARDS in the future.

scholarly journals Electroacupuncture Pretreatment Alleviates LPS-Induced Acute Respiratory Distress Syndrome via Regulating the PPAR Gamma/NF-Kappa B Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Di Feng ◽  
Huanping Zhou ◽  
Xiaohong Jin ◽  
Juan Wei ◽  
Qingqing Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Distress Syndrome ◽  
Ppar Gamma ◽  
Male Rats ◽  
Anti Inflammatory

Electroacupuncture (EA) is reported to possess anti-inflammatory properties and has beneficial effects on acute respiratory distress syndrome (ARDS). However, the underlying mechanisms of the effects of EA on ARDS remain unclear. This study aims to investigate the protective effect of EA on LPS-induced ARDS. In this study, Sprague-Dawley male rats were treated with EA at Hegu (LI4) for 45 minutes before LPS instillation (0.4 mg/kg, 100 ul). H&E staining, wet-to-dry weight (W/D) ratio, PaO2, and protein content in BALF were employed to determine the function of lung tissues. Inflammatory cytokines in serum and BALF were detected by enzyme-linked immunoassay assay (ELISA). The levels of oxidative stress markers were detected to determine the oxidative stress status. Cell apoptosis was observed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and western blot. Here, we found that EA pretreatment effectively alleviated lung pathological damage. Moreover, EA suppressed the oxidative stress damage by upregulating glutathione and superoxide dismutase and downregulating malondialdehyde. EA pretreatment also regulated apoptosis-related proteins, such as Bax and Bcl-2. We found that peroxisome proliferators-activated receptors γ (PPARγ) play a critical role during ARDS, EA up-regulated the expression of PPARγ, which inhibited the activation of nuclear factor-kappa B (NF-κB) and decreased the inflammatory cytokines (interleukin-1β, interleukin-6, and tumor necrosis factor-α). When rats were treated with GW9662, a selective PPARγ antagonist, these effects of EA were reversed. Our study demonstrated that EA pretreatment had a beneficial effect on LPS-induced ARDS in rats by anti-inflammatory, antioxidative, and antiapoptotic properties which was regulated via PPARγ/NF-κB signaling pathway.

Sign in / Sign up

Export Citation Format

Share Document