scholarly journals Inhibition of ERRα Aggravates Sepsis-Induced Acute Lung Injury in Rats via Provoking Inflammation and Oxidative Stress

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Wenfang Xia ◽  
Zhou Pan ◽  
Huanming Zhang ◽  
Qingshan Zhou ◽  
Yu Liu
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Cecal Ligation ◽  
Endothelial Permeability ◽  
Inflammatory Factors ◽  
Inflammatory Factor ◽  
Junction Protein ◽  
And Oxidative Stress

Inflammation and oxidative stress are critical pathologies that contribute to sepsis-induced acute lung injury (ALI). This study investigated the regulatory role of estrogen-related receptor alpha (ERRα) in an experimental model of sepsis-induced ALI. In vivo, a cecal ligation and puncture- (CLP-) induced ALI model was established in anesthetized rats. Animals were then randomly assigned to receive an intraperitoneal injection of vehicle or ERRα inverse agonist (XCT-790, 2.5 mg/kg). Administration of XCT-790 significantly aggravated a sepsis-induced increase in pathological damage of lung tissues, lung endothelial permeability, myeloperoxidase (MPO) activity in lung tissues, production of serum inflammatory factors, and inflammatory cell accumulation in bronchoalveolar lavage fluid. In addition, XCT-790 treatment exacerbated a CLP-induced decrease in lung superoxide dismutase and an increase in lung malondialdehyde levels. In vitro, the exposure of rat pulmonary microvascular endothelial cells (PMVECs) to lipopolysaccharide (LPS) resulted in increased endothelial permeability and reduced expression of tight junction protein ZO-1, Occludin, JAM-A, and adherens junction protein VE-cadherin, which were further deteriorated by knockdown of ERRα. In addition, LPS-triggered inflammatory factor production and increase in the expression of phosphorylated IκBα and NF-κB p65 were also exacerbated by silencing ERRα gene. Meanwhile, knockdown of ERRα dramatically promoted LPS-activated mitochondrial reactive oxygen species production and LPS-induced downregulation of Sirt3 protein levels in rat PMVECs. Taken together, our present study provides evidences that ERRα functions as a novel negative modulator of sepsis-induced ALI in rats. The underlying mechanisms responsible for ERRα-elicited effects are largely dependent on the regulation of inflammatory response and oxidative stress.

scholarly journals Down-regulation of SNHG16 alleviates the acute lung injury in sepsis rats through miR-128-3p/HMGB3 axis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Junli Sun ◽  
Keke Xin ◽  
Chenghui Leng ◽  
Jianlin Ge
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Western Blot ◽  
Cell Viability ◽  
Inflammatory Diseases ◽  
Cecal Ligation ◽  
Inflammatory Factors ◽  
Lung Epithelial

Abstract Background Long noncoding RNAs contribute to various inflammatory diseases, including sepsis. We explore the role of small nucleolar RNA host gene 16 (SNHG16) in sepsis-mediated acute lung injury (ALI) and inflammation. Methods A sepsis-induced ALI rat model was constructed by the cecal ligation and perforation method. The profiles of SNHG16, miR-128-3p, and high-mobility group box 3 (HMGB3) were monitored by quantitative reverse transcription PCR and Western blot. The pathologic changes of lung tissues were evaluated by Hematoxylin–Eosin staining, immunohistochemistry, and dry and wet method. Meanwhile, the pro-inflammatory factors and proteins were determined by ELISA and Western blot. In contrast, a sepsis model in BEAS-2B was induced with lipopolysaccharide (LPS) to verify the effects of SNHG16/miR-128-3p/HMGB3 on lung epithelial cell viability and apoptosis. Results As a result, SNHG16 and HMGB3 were up-regulated, while miR-128-3p was down-regulated in sepsis-induced ALI both in vivo and in vitro. Inhibiting SNHG16 reduced the apoptosis and inflammation in the sepsis-induced ALI model. Overexpressing SNHG16 promoted LPS-mediated lung epithelial apoptosis and inhibited cell viability and inflammation, while miR-128-3p had the opposite effects. Mechanistically, SNHG16 targeted miR-128-3p and attenuated its expression, while miR-128-3p targeted the 3′ untranslated region of HMGB3. Conclusions Overall, down-regulating SNHG16 alleviated the sepsis-mediated ALI by regulating miR-128-3p/HMGB3.

Isoacteoside Attenuates Septic Acute Lung Injury by Inhibiting Inflammation, Oxidative Stress and Endothelial Hyperpermeability in Mice

2021 ◽  
Author(s):  
Yan-nian Luo ◽  
Nan-nan He ◽  
Juan Xu ◽  
Rui Wang ◽  
Wen Cao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Survival Rate ◽  
Lung Injury ◽  
Cecal Ligation ◽  
Endothelial Permeability ◽  
Mouse Serum ◽  
Control Group ◽  
Expression Levels ◽  
Endothelial Hyperpermeability

Abstract The present study was aimed to explore the protective role of isoacteoside (ISO) in cecal ligation and puncture (CLP)-induced acute lung injury (ALI) in mice. Mice were divided into the following groups: sham control group, ALI group, and ALI+ISO group, in which mice received 10,50 or 100 mg/kg/day of ISO for 3 days before, 0h and 12h after CLP surgery. In the first experiment, all mice were maintained until 72 h after the CLP operation to calculate the survival rate. In the second experiment, mouse serum and lung and bronchoalveolar lavage fluid (BALF) were collected 24 h after model establishment for detection. The results revealed that ISO significantly improved the ALI associated survival rate, reduced the pathological injury, ALI score, infiltration of inflammatory cells, leakage of cells and proteins into BALF, systemic and local cytokine secretion, and pulmonary oxidative stress. Moreover, ISO significantly inhibited the expression levels of the pro-inflammatory proteins TLR4, MyD88, p-NF-κB p65, p-IKKαβ, and p-IκBα and increased the expression levels of the endothelial permeability related proteins ZO-1, claudin 5 and VE-cadherin. In conclusions, ISO mitigated acute lung injury in mice which was attributed to the capacity of ISO to inhibit inflammation, oxidative stress and endothelial hyperpermeability.

scholarly journals Mucin1 relieves acute lung injury by inhibiting inflammation and oxidative stress

2021 ◽  
Vol 65 (4) ◽  
Author(s):  
Chunlin Ye ◽  
Bin Xu ◽  
Jie Yang ◽  
Yunkun Liu ◽  
Zhikai Zeng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Respiratory Distress ◽  
Signaling Pathway ◽  
Lung Tissue ◽  
Inflammatory Factors ◽  
Mouse Lung ◽  
Muc1 Gene ◽  
And Oxidative Stress

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a kind of diffuse inflammatory injury caused by various factors, characterized by respiratory distress and progressive hypoxemia. It is a common clinical critical illness. The aim of this study was to investigate the effect and mechanism of the Mucin1 (MUC1) gene and its recombinant protein on lipopolysaccharide (LPS)-induced ALI/ARDS. We cultured human alveolar epithelial cell line (BEAS-2B) and used MUC1 overexpression lentivirus to detect the effect of MUC1 gene on BEAS-2B cells. In addition, we used LPS to induce ALI/ARDS in C57/BL6 mice and use hematoxylin and eosin (H&E) staining to verify the effect of their modeling. Recombinant MUC1 protein was injected subcutaneously into mice. We examined the effect of MUC1 on ALI/ARDS in mice by detecting the expression of inflammatory factors and oxidative stress molecules in mouse lung tissue, bronchoalveolar lavage fluid (BALF) and serum. Overexpression of MUC1 effectively ameliorated LPS-induced damage to BEAS-2B cells. Results of H&E staining indicate that LPS successfully induced ALI/ARDS in mice and MUC1 attenuated lung injury. MUC1 also reduced the expression of inflammatory factors (IL-1β, TNF-α, IL-6 and IL-8) and oxidative stress levels in mice. In addition, LPS results in an increase in the activity of the TLR4/NF-κB signaling pathway in mice, whereas MUC1 decreased the expression of the TLR4/NF-κB signaling pathway. MUC1 inhibited the activity of TLR4/NF-κB signaling pathway and reduced the level of inflammation and oxidative stress in lung tissue of ALI mice.

scholarly journals Tanreqing Inhibits LPS-Induced Acute Lung Injury In Vivo and In Vitro Through Downregulating STING Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Yu-Qiong He ◽  
Can-Can Zhou ◽  
Jiu-Ling Deng ◽  
Liang Wang ◽  
Wan-Sheng Chen
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Lung Edema ◽  
Protective Effects ◽  
And Oxidative Stress

Acute lung injury (ALI) is a common life-threatening lung disease, which is mostly associated with severe inflammatory responses and oxidative stress. Tanreqing injection (TRQ), a Chinese patent medicine, is clinically used for respiratory-related diseases. However, the effects and action mechanism of TRQ on ALI are still unclear. Recently, STING as a cytoplasmic DNA sensor has been found to be related to the progress of ALI. Here, we showed that TRQ significantly inhibited LPS-induced lung histological change, lung edema, and inflammatory cell infiltration. Moreover, TRQ markedly reduced inflammatory mediators release (TNF-α, IL-6, IL-1β, and IFN-β). Furthermore, TRQ also alleviated oxidative stress, manifested by increased SOD and GSH activities and decreased 4-HNE, MDA, LDH, and ROS activities. In addition, we further found that TRQ significantly prevented cGAS, STING, P-TBK, P-P65, P-IRF3, and P-IκBα expression in ALI mice. And we also confirmed that TRQ could inhibit mtDNA release and suppress signaling pathway mediated by STING in vitro. Importantly, the addition of STING agonist DMXAA dramatically abolished the protective effects of TRQ. Taken together, this study indicated that TRQ alleviated LPS-induced ALI and inhibited inflammatory responses and oxidative stress through STING signaling pathway.

scholarly journals miR-128-3p reduced acute lung injury induced by sepsis via targeting PEL12

Open Medicine ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. 1109-1120
Author(s):  
Shinan Liu ◽  
Shuai Gao ◽  
Zhaoyu Yang ◽  
Peng Zhang
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Caspase 3 ◽  
Lentiviral Vector ◽  
Cecal Ligation ◽  
Alveolar Epithelium ◽  
Luciferase Reporter ◽  
Inflammatory Factor ◽  
Apoptosis Rate

Abstract Objective Acute lung injury (ALI) caused by sepsis is clinically a syndrome, which is featured by damage to the alveolar epithelium and endothelium. In this study, we employed mice models of cecal ligation and puncture (CLP) and primary mice pulmonary microvascular endothelial cells (MPVECs) in vitro to investigate the effect of miR-128-3p in ALI caused by sepsis. Methods miR-128-3p agomir or randomized control were injected into adult male C57BL/6 mice 1 week before the CLP surgery. We used miR-128-3p agomir or scrambled control to transfect MPVECs and then employed lipopolysaccharide (LPS) stimulation on the cells. Pellino homolog 2 (PELI2) was predicted to be a direct target of miR-128-3p via luciferase reporter assay. MPVECs were cotransfected with lentiviral vector that expressed PELI2 (or empty vector) as well as miR-128-3p-mimics 1 day before LPS stimulation in rescue experiment. Transcriptional activity of caspase-3, cell apoptosis rate, and the expression levels of miR-128-3p, interleukin-1β (IL-1β), interleukin-6 (IL-6), and PELI2 were analyzed. Results Compared with the sham group, the lung of mice in the CLP group showed pulmonary morphological abnormalities, and the expression of IL-6 and IL-1β, caspase-3 activity, and apoptosis rate were significantly upregulated in the CLP group. Inflammatory factor levels and apoptosis rate were also significantly induced by LPS stimulation on MPVECs. Upregulation of miR-128-3p effectively inhibited sepsis-induced ALI, apoptosis as well as inflammation. miR-128-3p also played a role in antiapoptosis and anti-inflammation in MPVECs with LPS treatment. PEL12 upregulation in MPVECs alleviated miR-128-3p-induced caspase-3 activity inhibition and pro-inflammatory factor production. Conclusions miR-128-3p enabled to alleviate sepsis-induced ALI by inhibiting PEL12 expression, indicating a novel treatment strategy of miR-128-3p for sepsis-induced ALI.

scholarly journals Fn14 Exacerbates Acute Lung Injury by Activating the NLRP3 Inflammasome in Mice

2021 ◽  
Author(s):  
Xin-Xin Guan ◽  
Hui-Hui Yang ◽  
Wen-Jing Zhong ◽  
Jia-Xi Duan ◽  
Chen-Yu Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Survival Rate ◽  
Lung Injury ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Inflammatory Factor ◽  
Caspase 1 ◽  
Primary Mouse

Abstract Background: Uncontrolled inflammation is an important factor in the occurrence and development of acute lung injury (ALI). Fibroblast growth factor-inducible 14 (Fn14) takes part in the pathological process of a variety of inflammatory diseases. However, the role of Fn14 in ALI has not yet been elucidated. Methods: C57BL/6J mice were used in this study. ALI model was induced by intratracheal injection of lipopolysaccharide (LPS, 5 mg/kg). The effects of Fn14 receptor blocker ATA (20 mg/kg) on lung injury, inflammatory cell infiltration, inflammatory factor secretion, and oxidative stress in mice were observed. The activation of NLRP3 inflammasome was detected by qPCR, Western blot, and ELISA. Prophylactic or therapeutic ATA was administered to observe its effect on the survival rate of ALI mice. In vitro, primary mouse peritoneal macrophages were used to activate the NLRP3 inflammasome by LPS or LPS+ATP. Fn14 was activated by recombinant TWEAK, or knockdown by lentivirus, and the effects on NLRP3 inflammasome activation was detected.Results: We found that ATA significantly downregulated the expression of Fn14 in the lungs and improved the survival rate of mice receiving a lethal dose of LPS. ATA also attenuated lung tissue damage by decreasing the infiltration of macrophages and neutrophils, reducing inflammation, and suppressing oxidative stress. Interestingly, we found that ATA strongly inhibited the activation of NLRP3 inflammasome in the lungs of ALI mice. Furthermore, in vitro, exogenous TWEAK, a natural ligand of Fn14, enhanced the levels of NLRP3 and Caspase-1 p10 and the maturation and secretion of IL-1β in the primary murine macrophages, eventually leading to the activation of NLRP3 inflammasome. In addition, the expression of Fn14, NLRP3, and Caspase-1 p10 and the production of IL-1β were effectively blocked by Fn14 shRNA in macrophages. In mechanism, the activation of Fn14 promoted the production of reactive oxygen species in activated macrophages. Conclusion：Our study first reports that the activation of Fn14 aggravates ALI by amplifying the activation of NLRP3 inflammasome. Therefore, blocking Fn14 may be a potential way to treat ALI.

scholarly journals Oxypaeoniflorin Prevents Acute Lung Injury Induced by Lipopolysaccharide through the PTEN/AKT Pathway in a Sirt1-Dependent Manner

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Fan Guohua ◽  
Zhu Tieyuan ◽  
Wang Rui ◽  
Xiong Juan
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Alveolar Epithelial Cells ◽  
Dependent Manner ◽  
Alveolar Epithelial ◽  
And Oxidative Stress

Acute lung injury (ALI) is featured by pulmonary edema, alveolar barrier injury, inflammatory response, and oxidative stress. The activation of Sirt1 could relieve lipopolysaccharide- (LPS-) induced murine ALI by maintaining pulmonary epithelial barrier function. Oxypaeoniflorin (Oxy) serves as a major component of Paeonia lactiflora Pall., exerting cardioprotection by activating Sirt1. However, the role of Oxy in ALI induced by LPS remains unclear. The aim of the present study is to illustrate the modulatory effects and molecular mechanisms by which Oxy operates in ALI induced by LPS. The intraperitoneal injection of LPS was performed to establish the murine ALI model while LPS-treated alveolar epithelial cells were used to mimic the in vitro ALI model. Levels of lung injury, oxidative stress, and inflammatory response were detected to observe the potential effects of Oxy on ALI. Oxy treatment mitigated lung edema, inflammatory response, and oxidative stress in mouse response to LPS, apart from improving 7-day survival. Meanwhile, Oxy also increased the expression and activity of Sirt1. Intriguingly, Sirt1 deficiency or inhibition counteracted the protective effects of Oxy treatment in LPS-treated mice or LPS-treated alveolar epithelial cells by regulating the PTEN/AKT signaling pathway. These results demonstrated that Oxy could combat ALI in vivo and in vitro through inhibiting inflammatory response and oxidative stress in a Sirt1-dependent manner. Oxy owns the potential to be a promising candidate against ALI.

scholarly journals Moesin Is a Novel Biomarker of Endothelial Injury in Sepsis

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Yikun Chen ◽  
Jiajia Wang ◽  
Lei Zhang ◽  
Jianjie Zhu ◽  
Yuanyuan Zeng ◽  
...  
Keyword(s):  
Lung Injury ◽  
Cecal Ligation ◽  
Lavage Fluid ◽  
Endothelial Injury ◽  
Inflammatory Factors ◽  
Inflammatory Factor ◽  
Protein Levels ◽  
Potential Biomarker ◽  
The Impact

Objective. Increased vascular permeability and inflammation are principal hallmark of sepsis. Moesin (MSN) is a membrane-associated cytoskeleton protein and crucial for the vascular endothelial function. This study is aimed at evaluating the role of MSN in endothelial injury during the process of sepsis. Methods. Serum MSN in septic patients was measured by ELISA. BALB/c mice were injected with different doses of lipopolysaccharide (LPS) or underwent cecal ligation and single or double puncture (CLP) to mimic sublethal and lethal sepsis. After treatment, their serum MSN and PCT levels, wet to dry lung weights (W/D ratio), bronchoalveolar lavage fluid (BALF) protein concentrations, and lung injury scores were measured. The impact of MSN silencing on LPS-altered Rock1/myosin light chain (MLC), NF-κB, and inflammatory factors in human microvascular endothelial cells (HMECs), as well as monolayer HMEC permeability, was tested in vitro. Results. Compared with healthy controls, serum MSN increased in septic patients and was positively correlated with SOFA scores and serum PCT levels in septic patients. LPS injection significantly increased serum the MSN and PCT expression, BALF protein levels, and W/D ratio, and the serum MSN levels were positively correlated with serum PCT, lung W/D ratio, and lung injury scores in mice. Similar results were obtained in the way of CLP modelling. LPS enhanced MSN, MLC, NF-κB phosphorylation, increased Rock1 expression, and inflammatory factors release in the cultured HMECs, while MSN silencing significantly mitigated the LPS-induced Rock1 and inflammatory factor expression, NF-κB, and MLC phosphorylation as well as the monolayer hyperpermeability in HMECs. Conclusions. Increased serum MSN contributes to the sepsis-related endothelium damages by activating the Rock1/MLC and NF-κB signaling and may be a potential biomarker for evaluating the severity of sepsis.

scholarly journals In vitro and in vivo assessment of the protective effect of sufentanil in acute lung injury

2021 ◽  
Vol 49 (2) ◽  
pp. 030006052098635
Author(s):  
Qi Gao ◽  
Ningqing Chang ◽  
Donglian Liu
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Protective Effect ◽  
High Mobility ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Inflammatory Factors ◽  
Luciferase Reporter ◽  
Hmgb1 Protein

Objectives To investigate the mechanisms underlying the protective effect of sufentanil against acute lung injury (ALI). Material and Methods Rats were administered lipopolysaccharide (LPS) by endotracheal instillation to establish a model of ALI. LPS was used to stimulate BEAS-2B cells. The targets and promoter activities of IκB were assessed using a luciferase reporter assay. Apoptosis of BEAS-2B cells was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling. Results Sufentanil treatment markedly reduced pathological changes in lung tissue, pulmonary edema and secretion of inflammatory factors associated with ALI in vivo and in vitro. In addition, sufentanil suppressed apoptosis induced by LPS and activated NF-κB both in vivo and in vitro. Furthermore, upregulation of high mobility group box protein 1 (HMGB1) protein levels and downregulation of miR-129-5p levels were observed in vivo and in vitro following sufentanil treatment. miR-129-5p targeted the 3ʹ untranslated region and its inhibition decreased promoter activities of IκB-α. miR-129-5p inhibition significantly weakened the protective effect of sufentanil on LPS-treated BEAS-2B cells. Conclusion Sufentanil regulated the miR-129-5p/HMGB1 axis to enhance IκB-α expression, suggesting that sufentanil represents a candidate drug for ALI protection and providing avenues for clinical treatment.

scholarly journals Plasma extracellular vesicle delivery of miR-210-3p by targeting ATG7 to promote sepsis-induced acute lung injury by regulating autophagy and activating inflammation

2021 ◽  
Author(s):  
Guang Li ◽  
Bo Wang ◽  
Xiangchao Ding ◽  
Xinghua Zhang ◽  
Jian Tang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Recipient Cell ◽  
Cecal Ligation ◽  
Cell Permeability ◽  
Cell Counting ◽  
Inflammatory Factors ◽  
Luciferase Reporter ◽  
Enzyme Linked Immunosorbent Assay ◽  
Vascular Density

AbstractExtracellular vesicles (EVs) can be used for intercellular communication by facilitating the transfer of miRNAs from one cell to a recipient cell. MicroRNA (miR)-210-3p is released into the blood during sepsis, inducing cytokine production and promoting leukocyte migration. Thus, the current study aimed to elucidate the role of plasma EVs in delivering miR-210-3p in sepsis-induced acute lung injury (ALI). Plasma EVs were isolated from septic patients, after which the expression of various inflammatory factors was measured using enzyme-linked immunosorbent assay. Cell viability and apoptosis were measured via cell counting kit-8 and flow cytometry. Transendothelial resistance and fluorescein isothiocyanate fluorescence were used to measure endothelial cell permeability. Matrigel was used to examine the tubulogenesis of endothelial cells. The targeting relationship between miR-210-3p and ATG7 was assessed by dual-luciferase reporter assays. The expression of ATG7 and autophagy-related genes was determined to examine autophagic activation. A sepsis mouse model was established by cecal ligation and puncture (CLP)-induced surgery. The level of miR-210-3p was highly enriched in septic EVs. MiR-210-3p enhanced THP-1 macrophage inflammation, BEAS-2B cell apoptosis, and HLMVEC permeability while inhibiting angiogenesis and cellular activity. MiR-210-3p overexpression reduced ATG7 and LC3II/LC3I expression and increased P62 expression. Improvements in vascular density and autophagosome formation, increased ATG7 expression, and changes in the ratio of LC3II/LC3I were detected, as well as reduced P62 expression, in adenovirus-anti-miR-210-3p treated mice after CLP injury. Taken together, the key findings of the current study demonstrate that plasma EVs carrying miR-210-3p target ATG7 to regulate autophagy and inflammatory activation in a sepsis-induced ALI model.

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