The nanocomposite fullerol reduces oxidative stress, pulmonary injury, and mortality in a rat model of acute lung injury

BACKGROUND AND PURPOSE Acute lung injury (ALI) is a critical disorder that has high mortality rates, and pharmacological therapies are so far ineffective. The pathophysiology of ALI involves pulmonary oxidative stress and inflammatory response. Fullerol is a carbon nanocomposite that possesses antioxidant and anti-inflammatory properties. Here, we evaluated the therapeutic potential of fullerol and its mechanisms in a model of paraquat-induced ALI. EXPERIMENTAL APPROACH Rats were divided into ALI (paraquat alone), fullerol (paraquat plus fullerol), and control groups. Survival curves were estimated using the Kaplan-Meier method. The myeloperoxidase assay, ELISA, and hematoxylin and eosin staining were used to determine neutrophils infiltration, cytokines production, and histopathological parameters in lung samples, respectively. The antioxidant effect of fullerol was evaluated in vitro and ex vivo. KEY RESULTS Fullerol (0.01 to 0.3 mg/kg) markedly reduced the severe lung injury and high mortality rates observed in ALI rats. Moreover, fullerol (0.03 mg/kg) inhibited the reactive oxygen species formation and lipid peroxidation seen in lungs from ALI rats, and exhibited a potent concentration-dependent (10 to 10 mg/ml) in vitro antioxidant activity. Importantly, fullerol (0.03 mg/kg) inhibited neutrophils accumulation in bronchoalveolar lavage and lungs, and the increase in pulmonary levels of TNF-α, IL-1β, IL-6, and CINC-1 in ALI rats. CONCLUSIONS AND IMPLICATIONS Fullerol treatment was effective in reducing pulmonary damage and ALI-induced mortality, highlighting its therapeutic potential in an ALI condition. Searching for new pharmacological therapies to treat ALI may be desirable especially in view of the new coronavirus disease 2019 that currently plagues the world.

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Metformin-stimulated AMPK-α1 promotes microvascular repair in acute lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00173.2013 ◽

2013 ◽

Vol 305 (11) ◽

pp. L844-L855 ◽

Cited By ~ 47

Author(s):

Ming-Yuan Jian ◽

Mikhail F. Alexeyev ◽

Paul E. Wolkowicz ◽

Jaroslaw W. Zmijewski ◽

Judy R. Creighton

Keyword(s):

Endothelial Cells ◽

Acute Lung Injury ◽

Lung Injury ◽

Ex Vivo ◽

Endothelial Permeability ◽

Beneficial Effects ◽

Isolated Lung

Acute lung injury secondary to sepsis is a leading cause of mortality in sepsis-related death. Present therapies are not effective in reversing endothelial cell dysfunction, which plays a key role in increased vascular permeability and compromised lung function. AMP-activated protein kinase (AMPK) is a molecular sensor important for detection and mediation of cellular adaptations to vascular disruptive stimuli. In this study, we sought to determine the role of AMPK in resolving increased endothelial permeability in the sepsis-injured lung. AMPK function was determined in vivo using a rat model of endotoxin-induced lung injury, ex vivo using the isolated lung, and in vitro using cultured rat pulmonary microvascular endothelial cells (PMVECs). AMPK stimulation using N1-(α-d-ribofuranosyl)-5-aminoimidizole-4-carboxamide or metformin decreased the LPS-induced increase in permeability, as determined by filtration coefficient ( Kf) measurements, and resolved edema as indicated by decreased wet-to-dry ratios. The role of AMPK in the endothelial response to LPS was determined by shRNA designed to decrease expression of the AMPK-α1 isoform in capillary endothelial cells. Permeability, wounding, and barrier resistance assays using PMVECs identified AMPK-α1 as the molecule responsible for the beneficial effects of AMPK in the lung. Our findings provide novel evidence for AMPK-α1 as a vascular repair mechanism important in the pulmonary response to sepsis and identify a role for metformin treatment in the management of capillary injury.

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Biocompatible N-acetyl-nanoconstruct alleviates lipopolysaccharide-induced acute lung injury in vivo

Scientific Reports ◽

10.1038/s41598-021-01624-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Seongchan Kim ◽

Shin Young Kim ◽

Seung Joon Rho ◽

Seung Hoon Kim ◽

So Hyang Song ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Intratracheal Instillation ◽

Sprague Dawley ◽

In Vivo Experiments ◽

Anti Inflammatory

AbstractOxidative stress plays important roles in inflammatory responses during acute lung injury (ALI). Recently, nanoconstruct (Nano)-based drug-delivery systems have shown promise in many models of inflammation. In this study, we evaluated the anti-inflammatory effects of N-acetylcysteine (NAC) loaded in a biocompatible Nano using a rat model of ALI. We synthesized a Nano with a good NAC-releasing capacity using porous silica Nano, which was used to produce Nano/NAC complexes. For in vivo experiments, Sprague–Dawley rats were intraperitoneally administered NAC or Nano/NAC 30 min after intratracheal instillation of lipopolysaccharide. After 6 h, bronchoalveolar lavage fluids and lung tissues were collected. The anti-oxidative effect of the Nano/NAC complex was confirmed by demonstrating reduced levels of reactive oxygen species after treatment with the Nano/NAC in vitro. In vivo experiments also showed that the Nano/NAC treatment may protect against LPS‐induced ALI thorough anti‐oxidative and anti‐inflammatory effects, which may be attributed to the inactivation of the NF‐κB and MAPK pathways. In addition, the effects of Nano/NAC treatment were shown to be superior to those of NAC alone. We suggest the therapeutic potential of Nano/NAC treatment as an anti‐inflammatory agent against ALI. Furthermore, our study can provide basic data for developing nanotechnology-based pharmacotherapeutics for ALI.

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Spiraea prunifolia var. simpliciflora Attenuates Oxidative Stress and Inflammatory Responses in a Murine Model of Lipopolysaccharide-Induced Acute Lung Injury and TNF-α-Stimulated NCI-H292 Cells

Antioxidants ◽

10.3390/antiox9030198 ◽

2020 ◽

Vol 9 (3) ◽

pp. 198 ◽

Cited By ~ 1

Author(s):

Ba-Wool Lee ◽

Ji-Hye Ha ◽

Han-Gyo Shin ◽

Seong-Hun Jeong ◽

Da-Bin Jeon ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Lung Injury ◽

Lung Injury ◽

Nuclear Translocation ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Herbal Remedy ◽

Related Factor ◽

Nuclear Factor ◽

Tnf Α

Spiraea prunifolia var. simpliciflora (SP) is traditionally used as an herbal remedy to treat fever, malaria, and emesis. This study aimed to evaluate the anti-oxidative and anti-inflammatory properties of the methanol extract of SP leaves in tumor necrosis factor (TNF)-α-stimulated NCI-H292 cells and in a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model. SP decreased the number of inflammatory cells and the levels of TNF-α, interleukin (IL)-1β, and IL-6 in the bronchoalveolar lavage fluid, and inflammatory cell infiltration in the lung tissues of SP-treated mice. In addition, SP significantly suppressed the mRNA and protein levels of TNF-α, IL-1β, and IL-6 in TNF-α-stimulated NCI-H292 cells. SP significantly suppressed the phosphorylation of the mitogen-activated protein kinases (MAPKs) and p65-nuclear factor-kappa B (NF-κB) in LPS-induced ALI mice and TNF-α-stimulated NCI-H292 cells. SP treatment enhanced the nuclear translocation of nuclear factor erythroid 2-related factor (Nrf2) with upregulated antioxidant enzymes and suppressed reactive oxygen species (ROS)-mediated oxidative stress in the lung tissues of LPS-induced ALI model and TNF-α-stimulated NCI-H292 cells. Collectively, SP effectively inhibited airway inflammation and ROS-mediated oxidative stress, which was closely related to its ability to induce activation of Nrf2 and inhibit the phosphorylation of MAPKs and NF-κB. These findings suggest that SP has therapeutic potential for the treatment of ALI.

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/2048632 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9 ◽

Cited By ~ 2

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.

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

Frontiers in Pharmacology ◽

10.3389/fphar.2021.746964 ◽

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.

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Honokiol alleviates LPS-induced acute lung injury by inhibiting NLRP3 inflammasome-mediated pyroptosis via Nrf2 activation in vitro and in vivo

10.21203/rs.3.rs-917410/v1 ◽

2021 ◽

Author(s):

yuhan liu ◽

jiabin zhou ◽

yingying luo ◽

jinxiao li ◽

luorui shang ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Lung Injury ◽

Lung Injury ◽

Nlrp3 Inflammasome ◽

Epithelial Cell Line ◽

Protective Mechanism ◽

Expression Levels ◽

Nrf2 Activation

Abstract Background Honokiol (HKL) has been reported to ameliorate lipopolysaccharide (LPS)-induced acute lung injury (ALI). However, its potential mechanism imparting the protective effects remains unclear. In this study, the protective mechanism of HKL on LPS-induced ALI was explored in vivo and in vitro. Methods In vivo, the SD rats were intratracheally instilled with LPS (5 mg/kg) to establish an acute lung injury model and then treated with HKL (1.25/2.5/5 mg/kg) or ML385 (30 mg/kg) intraperitoneally. In vitro, the human bronchial epithelial cell line (BEAS-2B) was stimulated with LPS and ATP to induce pyroptosis and treated with HKL (12.5/25/50 µM). Small interfering RNA (siRNA) technique was used to knockdown Nrf2 in BEAS-2B cells. The protein and mRNA expression levels of Nrf2, HO-1, NLRP3, ASC, CASP1, and GSDMD in cells and lung tissues were detected by western blot and real time-PCR. The expression levels of interleukin (IL)-1β, IL-18, MPO, MDA, and SOD in bronchoalveolar lavage fluid (BALF) and supernatant were determined by ELISA. The degree of pathological injury of lung tissue was evaluated by H&E staining. Results The results showed that HKL could alleviate the oxidative stress and inflammatory responses by regulating the levels of MPO, MDA, SOD, IL-1β, IL-18 in supernatant. And HKL inhibited the expression levels of NLRP3, ASC, CASP1, GSDMD via activation of Nrf2 in BEAS-2B cells. Further studies revealed that HKL could attenuate the pathological injury in LPS-induced ALI rats and the molecular mechanism was consistent with the results in vitro. Conclusions Our study demonstrated that HKL could alleviate LPS-induced ALI by reducing the oxidative stress and inhibiting NLRP3 inflammasome-mediated pyroptosis, which was partly dependent on the Nrf2 activation.

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

10.21203/rs.3.rs-1005882/v1 ◽

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.

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Honokiol alleviates LPS-induced acute lung injury by inhibiting NLRP3 inflammasome-mediated pyroptosis via Nrf2 activation in vitro and in vivo

Chinese Medicine ◽

10.1186/s13020-021-00541-z ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Yuhan Liu ◽

Jiabin Zhou ◽

Yingying Luo ◽

Jinxiao Li ◽

Luorui Shang ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Lung Injury ◽

Lung Injury ◽

Nlrp3 Inflammasome ◽

Epithelial Cell Line ◽

Protective Mechanism ◽

Expression Levels ◽

Nrf2 Activation

Abstract Background Honokiol (HKL) has been reported to ameliorate lipopolysaccharide (LPS)-induced acute lung injury (ALI). However, its potential mechanism of its protective effects remains unclear. In this study, the protective mechanism of HKL on LPS-induced ALI was explored in vivo and in vitro. Methods In vivo, the SD rats were intratracheally instilled with LPS (5 mg/kg) to establish an acute lung injury model and then treated with HKL (1.25/2.5/5 mg/kg) or ML385 (30 mg/kg) intraperitoneally. In vitro, the human bronchial epithelial cell line (BEAS-2B) was stimulated with LPS and ATP to induce pyroptosis and treated with HKL (12.5/25/50 μM). Small interfering RNA (siRNA) technique was used to knockdown Nrf2 in BEAS-2B cells. The protein and mRNA expression levels of Nrf2, HO-1, NLRP3, ASC, CASP1, and GSDMD in cells and lung tissues were detected by western blot and real time-PCR. The expression levels of interleukin (IL)-1β, IL-18, MPO, MDA, and SOD in bronchoalveolar lavage fluid (BALF) and supernatant were determined by ELISA. The degree of pathological injury of lung tissue was evaluated by H&E staining. Results The results showed that HKL could alleviate oxidative stress and inflammatory responses by regulating the levels of MPO, MDA, SOD, IL-1β, IL-18 in supernatant. And it could also inhibit the expression levels of NLRP3, ASC, CASP1, GSDMD via activation of Nrf2 in BEAS-2B cells. Further studies revealed that HKL could attenuate the pathological injury in LPS-induced ALI rats, and the molecular mechanism was consistent with the results in vitro. Conclusions Our study demonstrated that HKL could alleviate LPS-induced ALI by reducing the oxidative stress and inhibiting NLRP3 inflammasome-mediated pyroptosis, which was partly dependent on the Nrf2 activation. Graphical Abstract

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Corylin Ameliorates LPS-Induced Acute Lung Injury via Suppressing the MAPKs and IL-6/STAT3 Signaling Pathways

Pharmaceuticals ◽

10.3390/ph14101046 ◽

2021 ◽

Vol 14 (10) ◽

pp. 1046

Author(s):

I-Chen Chen ◽

Shu-Chi Wang ◽

Yi-Ting Chen ◽

Hsin-Han Tseng ◽

Po-Len Liu ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Immune Cell ◽

Therapeutic Potential ◽

Lavage Fluid ◽

Mitogen Activated Protein ◽

Associated Proteins ◽

Anti Inflammatory

Acute lung injury (ALI) is a high mortality disease with acute inflammation. Corylin is a compound isolated from the whole plant of Psoralea corylifolia L. and has been reported to have anti-inflammatory activities. Herein, we investigated the therapeutic potential of corylin on lipopolysaccharides (LPS)-induced ALI, both in vitro and in vivo. The levels of proinflammatory cytokine secretions were analyzed by ELISA; the expressions of inflammation-associated proteins were detected using Western blot; and the number of immune cell infiltrations in the bronchial alveolar lavage fluid (BALF) were detected by multicolor flow cytometry and lung tissues by hematoxylin and eosin (HE) staining, respectively. Experimental results indicated that corylin attenuated LPS-induced IL-6 production in human bronchial epithelial cells (HBEC3-KT cells). In intratracheal LPS-induced ALI mice, corylin attenuated tissue damage, suppressed inflammatory cell infiltration, and decreased IL-6 and TNF-α secretions in the BALF and serum. Moreover, it further inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs), including p-JNK, p-ERK, p-p38, and repressed the activation of signal transducer and activator of transcription 3 (STAT3) in lungs. Collectively, our results are the first to demonstrate the anti-inflammatory effects of corylin on LPS-induced ALI and suggest corylin has significant potential as a novel therapeutic agent for ALI.

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Modelling Of Influenza A-Induced Acute Lung Injury (ALI) And Repair: The Development Of Novel Ex Vivo And In Vitro Models

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a1325 ◽

2012 ◽

Author(s):

Mark H. Almond ◽

Alastair G. Proudfoot ◽

Neeltje Van Doremalen ◽

Mark J. Griffiths ◽

Wendy S. Barclay

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Influenza A ◽

Ex Vivo ◽

In Vitro Models

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