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.

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 Hordenine Protects Against Lipopolysaccharide-Induced Acute Lung Injury by Inhibiting Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiyue Zhang ◽  
Li Du ◽  
Jinrong Zhang ◽  
Chunyan Li ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Protein Kinase ◽  
Lung Injury ◽  
Biological Activities ◽  
Mitogen Activated Protein Kinase ◽  
Inflammatory Factors ◽  
Enzyme Linked Immunosorbent Assay ◽  
Anti Inflammatory

Acute lung injury (ALI) is a respiratory disease that leads to death in severe cases. Hordenine (Hor), a barley-derived natural product, has various biological activities, including anti-inflammatory, and anti-oxidation activities. We investigated the effect of Hor on lipopolysaccharide-induced ALI and its potential mechanism. The anti-inflammatory effects of Hor were detected using in vivo and in vitro models by enzyme-linked immunosorbent assay, real-time polymerase chain reaction, western blotting, and molecular docking simulations. Hor inhibited increases in the levels of inflammatory factors both in vivo and in vitro, and its anti-inflammatory effect inhibited activation of protein kinase B, nuclear factor-κB, and mitogen-activated protein kinase signaling. Hor alleviated lipopolysaccharide-induced ALI by inhibiting inflammatory cytokine increases in vivo and in vitro and shows potential for preventing inflammatory disease.

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 Discovery of a Novel MyD88 Inhibitor M20 and Its Protection Against Sepsis-Mediated Acute Lung Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiali Song ◽  
Daoxing Chen ◽  
Yingqiao Pan ◽  
Xueqin Shi ◽  
Qian Liu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Important Interaction ◽  
Receptor Signaling Pathway ◽  
Myeloid Differentiation Factor ◽  
Resonance Detection

Myeloid differentiation factor 88 (MyD88) is a hub protein in the Toll-like receptor signaling pathway, which acts as a master switch for numerous inflammatory diseases, including acute lung injury (ALI). Although this protein is considered as a crucial therapeutic target, there are currently no clinically approved MyD88-targeting drugs. Based on previous literature, here we report the discovery via computer-aided drug design (CADD) of a small molecule, M20, which functions as a novel MyD88 inhibitor to efficiently relieve lipopolysaccharide-induced inflammation both in vitro and in vivo. Computational chemistry, surface plasmon resonance detection (SPR) and biological experiments demonstrated that M20 forms an important interaction with the MyD88-Toll/interleukin-1 receptor domain and thereby inhibits the protein dimerization. Taken together, this study found a MyD88 inhibitor, M20, with a novel skeleton, which provides a crucial understanding in the development and modification of MyD88 inhibitors. Meanwhile, the favorable bioactivity of the hit compound is also conducive to the treatment of acute lung injury or other more inflammatory diseases.

scholarly journals Exosomes Derived From Alveolar Epithelial Cells Promote Alveolar Macrophage Activation Mediated by miR-92a-3p in Sepsis-Induced Acute Lung Injury

2021 ◽  
Vol 11 ◽  
Author(s):  
Fen Liu ◽  
Wei Peng ◽  
Jiaquan Chen ◽  
Zeyao Xu ◽  
Rong Jiang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Pulmonary Inflammation ◽  
Cecal Ligation ◽  
Alveolar Epithelial Cells ◽  
Luciferase Reporter ◽  
Alveolar Epithelial

Acute lung injury (ALI) induced by sepsis is characterized by disruption of the epithelial barrier and activation of alveolar macrophages (AMs), which leads to uncontrolled pulmonary inflammation. However, effective treatments for ALI are unavailable. The exact mechanism by which the initial mediator of alveolar epithelial cells (AECs) induces inflammation remains elusive. Here we investigated the roles of AEC-derived exosomes in AM activation and sepsis-induced ALI in vivo and in vitro. Cecal ligation and puncture (CLP) was utilized to establish septic lung injury model in rats. The effect of exosomal inhibition by intratracheal GW4869 administration on lung injury was investigated. To assess the effects of AEC-derived exosomes on ALI, we treated the rat alveolar epithelial cell line RLE-6TN with LPS to induce cell damage. Exosomes from conditioned medium of LPS-treated AECs (LPS-Exos) were isolated by ultracentrifugation. The miRNAs in LPS-Exos were screened by miRNA expression profile analysis. The effects of miR-92a-3p on the function of AMs were studied. We found that intratracheal GW4869 administration ameliorated lung injury following CLP-induced ALI. LPS-Exos were taken up by AMs and activated these cells. Consistently, administration of LPS-Exos in rats significantly aggravated pulmonary inflammation and alveolar permeability. Moreover, miR-92a-3p was enriched in LPS-Exos and could be delivered to AMs. Inhibition of miR-92a-3p in AECs diminished the proinflammatory effects of LPS-Exos in vivo and in vitro. Mechanistically, miR-92a-3p activates AMs along with pulmonary inflammation. This process results in activation of the NF-κB pathway and downregulation of PTEN expression, which was confirmed by a luciferase reporter assay. In conclusion, AEC-derived exosomes activate AMs and induce pulmonary inflammation mediated by miR-92a-3p in ALI. The present findings revealed a previously unidentified role of exosomal miR-92a-3p in mediating the crosstalk between injured AEC and AMs. miR-92a-3p in AEC exosomes might represent a novel diagnostic biomarker for ALI, which may lead to a new therapeutic approach.

Two indole-2-carboxamide derivatives attenuate lipopolysaccharide-induced acute lung injury by inhibiting inflammatory response

2018 ◽  
Vol 96 (12) ◽  
pp. 1261-1267
Author(s):  
Wei Dai ◽  
Xiangting Ge ◽  
Tingting Xu ◽  
Chun Lu ◽  
Wangfeng Zhou ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Tissue ◽  
Inflammatory Diseases ◽  
Inflammatory Cells ◽  
Genes Expression ◽  
Tnf Α ◽  
Induced Changes

Acute lung injury (ALI) is the leading cause of mortality in the intensive care unit. Currently, there is no effective pharmacological treatment for ALI. In our previous study, we reported that Lg25 and Lg26, two indole-2-carboxamide derivatives, inhibited the lipopolysaccharide (LPS)-induced inflammatory cytokines in vitro and attenuated LPS-induced sepsis in vivo. In the present study, we confirmed data from previous studies that LPS significantly induced pulmonary edema and pathological changes in lung tissue, increased protein concentration and number of inflammatory cells in bronchoalveolar lavage fluids (BALF), and increased inflammatory cytokine TNF-α expression in serum and BALF, pro-inflammatory genes expression, and macrophages infiltration in lung tissue. However, pretreatment with Lg25 and Lg26 significantly attenuated the LPS-induced changes in mice. Taken together, these data indicate that the newly discovered indole-2-carboxamide derivatives could be particularly useful in the treatment of inflammatory diseases such as ALI.

scholarly journals MicroRNA-377-3p released by mesenchymal stem cell exosomes ameliorates lipopolysaccharide-induced acute lung injury by targeting RPTOR to induce autophagy

2020 ◽  
Vol 11 (8) ◽  
Author(s):  
Xuxia Wei ◽  
Xiaomeng Yi ◽  
Haijin Lv ◽  
Xin Sui ◽  
Pinglan Lu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Fetal Lung ◽  
Lung Damage ◽  
Inflammatory Factors ◽  
Human Umbilical Cord ◽  
Human Fetal Lung ◽  
Human Fetal Lung Fibroblast

Abstract Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the severe lung damage and respiratory failure without effective therapy. However, there was a lack of understanding of the mechanism by which exosomes regulate autophagy during ALI/ARDS. Here, we found lipopolysaccharide (LPS) significantly increased inflammatory factors, administration of exosomes released by human umbilical cord mesenchymal stem cells (hucMSCs) successfully improved lung morphometry. Further studies showed that miR-377-3p in the exosomes played a pivotal role in regulating autophagy, leading to protect LPS induced ALI. Compared to exosomes released by human fetal lung fibroblast cells (HFL-1), hucMSCs-exosomes overexpressing miR-377-3p more effectively suppressed the bronchoalveolar lavage (BALF) and inflammatory factors and induced autophagy, causing recoveration of ALI. Administration of miR-377-3p expressing hucMSCs-exosomes or its target regulatory-associated protein of mTOR (RPTOR) knockdown significantly reduced ALI. In summary, miR-377-3p released by hucMSCs-exosomes ameliorated Lipopolysaccharide-induced acute lung injury by targeting RPTOR to induce autophagy in vivo and in vitro.

Erythropoietin alleviates acute lung injury induced by ischemia-reperfusion through blocking p38 MAPK signaling

2021 ◽  
pp. 096032712110434
Author(s):  
Ling Jia ◽  
Wenjing Cui ◽  
Jiao Chen ◽  
Jinghui Yang ◽  
Xiang Xue ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Oxidative Damage ◽  
P38 Mapk ◽  
Ischemia Reperfusion ◽  
Mapk Signaling ◽  
Inflammatory Factors ◽  
Related Factors

Erythropoietin (EPO) has antiapoptotic, antioxidative, and anti-inflammatory effects on ischemia tissues and protects against acute lung injury (ALI) induced by ischemia-reperfusion (I/R). p38 mitogen-activated protein kinases (p38 MAPK) signaling is involved in the processes of I/R-induced ALI. However, the interaction of EPO with p38 MAPK signaling in I/R-induced ALI has not been reported. To explore this issue, we constructed an I/R-induced ALI model in vivo and in vitro using Sprague Dawley rats and BEAS-2B cells. Some I/R rats and hypoxia-reoxygenation (H/R)–induced cells were treated with EPO, and the others were used as control groups. The injuries of lung tissues and cells were respectively assessed by inflammatory cytokine, morphologic changes, cell viability, apoptosis, and oxidative damage–related factors. Western blot determined key proteins in the p38 MAPK signaling. Results indicated that I/R induced the increase of inflammatory factors, lung weight, filtration coefficient, bronchoalveolar lavage fluid protein content, apoptosis, neutrophil, and lung peroxidation, and H/R caused cell growth inhibition, apoptosis, and oxidative damage-related factors’ release. EPO attenuated I/R-induced injury in vivo and in vitro. Furthermore, the increase of p-p38, p-JNK, and p-ERK1/2 in lung tissues and cells induced by I/R was downregulated by EPO. Moreover, both EPO and an inhibitor of p38 MAPK (SB203580) alleviated H/R-induced cell injury. Erythropoietin along with SB203580 had more obvious protection effects than EPO alone. Collectively, EPO alleviated I/R-induced ALI by blocking p38 MAPK signaling. The interaction mechanism of EPO with p38 MAPK signaling contributes to understanding the processes of I/R-induced ALI and provides new insights for the disease treatment.

scholarly journals A Novel Protective Mechanism for Melatonin Against Acute Lung Injury: Preserving Mitochondrial Dynamic Equilibrium of Lung Epithelial Cells Through SIRT3-Dependent Deacetylation of SOD2

2022 ◽  
Author(s):  
Li Ning ◽  
Xiong Rui ◽  
Li Guorui ◽  
Fu Tinglv ◽  
Li Donghang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Dynamic Equilibrium ◽  
Lung Epithelial Cells ◽  
Mitochondrial Dynamic ◽  
Lung Epithelial

Abstract Mitochondrial dynamic equilibrium of lung epithelial cells is disturbed during sepsis, which contributes to abnormal mitochondrial function and acute lung injury (ALI). Melatonin is one primary hormone secreted by the pineal gland, displaying favorable antioxidative actions in sepsis and cardiopulmonary disease. However, the potential roles and molecular basis of melatonin in lipopolysaccharide (LPS)-treated lung epithelial cells have not been explored and reported. Herein, we investigated whether melatonin could protect against sepsis-induced ALI and lipopolysaccharide (LPS)-treated lung epithelial cells through mitochondrial dynamic equilibrium as well as its possible molecular targets. Wild type and Sirt3 knockout mice were instilled with LPS intratracheally for 12 hours to construct an in vivo ALI model. And A549 lung epithelial cells were used to explore the possible roles of melatonin in vitro by incubating with small interfering RNA (siRNA) against Sirt3. To figure out the involvement of melatonin receptor, si Mtnr1b and luzindole were used in cells and mice. Melatonin pretreatment significantly inhibited pathological injury, inflammatory response, oxidative stress and apoptosis in LPS-treated lung tissues and LPS-treated lung epithelial cells. Meanwhile, melatonin also shifted the dynamic course of mitochondria from fission into fusion in LPS-treated lung epithelial cells in vivo and in vitro. However, SIRT3 inhibition abolished the protective roles of melatonin in ALI. Mechanistically, we found that melatonin increased the activity and expression of SIRT3, which further promoted the deacetylation of SOD2 at K122 and K68. More importantly, melatonin exerted pulmonary protection by activating MTNR1B but not MTNR1A in ALI. Collectively, melatonin could preserve mitochondrial dynamic equilibrium of lung epithelial cells through the deacetylation of SOD2 in a SIRT3-dependent manner, which eventually alleviated LPS-elicited injury, inflammation, oxidative stress, apoptosis. Thus, melatonin may serve as a promising candidate against ALI in the future.

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