Nrf2 protects against drowning-induced acute lung injury via inhibiting ferroptosis

Abstract Background Drowning-induced acute lung injury (ALI) has been a major cause of accidental death worldwide. Severe oxidative stress injury is the key factor in drowning-induced ALI. The latest evidences indicate nuclear factor (erythroid-derived 2)-like 2 (Nrf2) suppress Ferroptosis and maintain cellular redox balance. Here, we test the hypothesis that activation of Nrf2 attenuates drowning-induced ALI via inhibiting ferroptosis. Methods In this study, we employed Nrf2-specific agonist (dimethyl fumarate), Nrf2 inhibitor (ML385), Nrf2-knockout mice and ferroptosis inhibitor (Ferrostatin-1) to investigate the beneficial roles of Nrf2 on drowning-induced ALI and the underlying mechanisms. Results In this study, we firstly showed that Nrf2 activator dimethyl fumarate could increase cell viability, reduced the levels of intracellular ROS and lipid ROS, prevented glutathione depletion and lipid peroxide accumulation, increased FTH1 and GPX4 mRNA expression, and maintained mitochondrial membrane potential. However, ML385 promoted cell death and lipid ROS production. Furthermore, Nrf2 knockout aggravated seawater drowning-induced ALI in mice. Conclusions In summary, these results suggest that Nrf2 alleviate drowning-induced ALI in MLE-12 cells and mice through inhibiting ferroptosis.

Download Full-text

Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis

Respiratory Research ◽

10.1186/s12931-020-01500-2 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Yu-bao Qiu ◽

Bin-bin Wan ◽

Gang Liu ◽

Ya-xian Wu ◽

Dan Chen ◽

...

Keyword(s):

Cell Death ◽

Acute Lung Injury ◽

Lung Injury ◽

Knockout Mice ◽

Lipid Peroxide ◽

Dimethyl Fumarate ◽

Redox Balance ◽

Glutathione Depletion ◽

Stress Injury ◽

Nrf2 Knockout

Abstract Background Ferroptosis is a new type of nonapoptotic cell death model that was closely related to reactive oxygen species (ROS) accumulation. Seawater drowning-induced acute lung injury (ALI) which is caused by severe oxidative stress injury, has been a major cause of accidental death worldwide. The latest evidences indicate nuclear factor (erythroid-derived 2)-like 2 (Nrf2) suppress ferroptosis and maintain cellular redox balance. Here, we test the hypothesis that activation of Nrf2 pathway attenuates seawater drowning-induced ALI via inhibiting ferroptosis. Methods we performed studies using Nrf2-specific agonist (dimethyl fumarate), Nrf2 inhibitor (ML385), Nrf2-knockout mice and ferroptosis inhibitor (Ferrostatin-1) to investigate the potential roles of Nrf2 on seawater drowning-induced ALI and the underlying mechanisms. Results Our data shows that Nrf2 activator dimethyl fumarate could increase cell viability, reduced the levels of intracellular ROS and lipid ROS, prevented glutathione depletion and lipid peroxide accumulation, increased FTH1 and GPX4 mRNA expression, and maintained mitochondrial membrane potential in MLE-12 cells. However, ML385 promoted cell death and lipid ROS production in MLE-12 cells. Furthermore, the lung injury became more aggravated in the Nrf2-knockout mice than that in WT mice after seawater drowning. Conclusions These results suggested that Nrf2 can inhibit ferroptosis and therefore alleviate ALI induced by seawater drowning. The effectiveness of ferroptosis inhibition by Nrf2 provides a novel therapeutic target for seawater drowning-induced ALI.

Download Full-text

Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis

10.21203/rs.3.rs-34579/v3 ◽

2020 ◽

Author(s):

Yu-bao Qiu ◽

Bin-bin Wan ◽

Gang Liu ◽

Ya-xian Wu ◽

Dan Chen ◽

...

Keyword(s):

Cell Death ◽

Acute Lung Injury ◽

Lung Injury ◽

Knockout Mice ◽

Lipid Peroxide ◽

Dimethyl Fumarate ◽

Redox Balance ◽

Glutathione Depletion ◽

Stress Injury ◽

Nrf2 Knockout

Abstract Background: Ferroptosis is a new type of nonapoptotic cell death model that was closely related to reactive oxygen species (ROS) accumulation. Seawater drowning-induced acute lung injury (ALI) which is caused by severe oxidative stress injury, has been a major cause of accidental death worldwide. The latest evidences indicate nuclear factor (erythroid-derived 2)-like 2 (Nrf2) suppress ferroptosis and maintain cellular redox balance. Here, we test the hypothesis that activation of Nrf2 pathway attenuates seawater drowning-induced ALI via inhibiting ferroptosis.Methods: we performed studies using Nrf2-specific agonist (dimethyl fumarate), Nrf2 inhibitor (ML385), Nrf2-knockout mice and ferroptosis inhibitor (Ferrostatin-1) to investigate the potential roles of Nrf2 on seawater drowning-induced ALI and the underlying mechanisms.Results: Our data shows that Nrf2 activator dimethyl fumarate could increase cell viability, reduced the levels of intracellular ROS and lipid ROS, prevented glutathione depletion and lipid peroxide accumulation, increased FTH1 and GPX4 mRNA expression, and maintained mitochondrial membrane potential in MLE-12 cells. However, ML385 promoted cell death and lipid ROS production in MLE-12 cells. Furthermore, the lung injury became more aggravated in the Nrf2-knockout mice than that in WT mice after seawater drowning.Conclusions: These results suggested that Nrf2 can inhibit ferroptosis and therefore alleviate ALI induced by seawater drowning. The effectiveness of ferroptosis inhibition by Nrf2 provides a novel therapeutic target for seawater drowning-induced ALI.

Download Full-text

Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis

10.21203/rs.3.rs-34579/v2 ◽

2020 ◽

Author(s):

Yu-bao Qiu ◽

Bin-bin Wan ◽

Gang Liu ◽

Ya-xian Wu ◽

Dan Chen ◽

...

Keyword(s):

Cell Death ◽

Acute Lung Injury ◽

Lung Injury ◽

Knockout Mice ◽

Lipid Peroxide ◽

Dimethyl Fumarate ◽

Redox Balance ◽

Glutathione Depletion ◽

Stress Injury ◽

Nrf2 Knockout

Abstract Background: Ferroptosis is a new type of nonapoptotic cell death model that was closely related to ROS accumulation. Seawater drowning-induced acute lung injury (ALI) which is caused by severe oxidative stress injury, has been a major cause of accidental death worldwide. The latest evidences indicate nuclear factor (erythroid-derived 2)-like 2 (Nrf2) suppress ferroptosis and maintain cellular redox balance. Here, we test the hypothesis that activation of Nrf2 pathway attenuates seawater drowning-induced ALI via inhibiting ferroptosis.Methods: we performed studies using Nrf2-specific agonist (dimethyl fumarate), Nrf2 inhibitor (ML385), Nrf2-knockout mice and ferroptosis inhibitor (Ferrostatin-1) to investigate the potential roles of Nrf2 on seawater drowning-induced ALI and the underlying mechanisms. Results: Our data shows that Nrf2 activator dimethyl fumarate could increase cell viability, reduced the levels of intracellular ROS and lipid ROS, prevented glutathione depletion and lipid peroxide accumulation, increased FTH1 and GPX4 mRNA expression, and maintained mitochondrial membrane potential in MLE-12 cells. However, ML385 promoted cell death and lipid ROS production in MLE-12 cells. Furthermore, the lung injury became more aggravated in the Nrf2-knockout mice than that in WT mice after seawater drowning. These findings may guide the development of a new therapeutic approach for seawater drowning-induced ALI Conclusions: These results suggested that Nrf2 can inhibit ferroptosis and therefore alleviate ALI induced by seawater drowning. The effectiveness of ferroptosis inhibition by Nrf2 provides a novel therapeutic target for seawater drowning-induced ALI.

Download Full-text

Acid sphingomyelinase mediates murine acute lung injury following transfusion of aged platelets

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00317.2016 ◽

2017 ◽

Vol 312 (5) ◽

pp. L625-L637 ◽

Cited By ~ 10

Author(s):

Mark J. McVey ◽

Michael Kim ◽

Arata Tabuchi ◽

Victoria Srbely ◽

Lukasz Japtok ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Pulmonary Complications ◽

Acid Sphingomyelinase ◽

Blood Products ◽

Barrier Dysfunction ◽

Neutrophil Accumulation ◽

Characteristic Features ◽

Underlying Mechanisms ◽

Stored Blood

Pulmonary complications from stored blood products are the leading cause of mortality related to transfusion. Transfusion-related acute lung injury is mediated by antibodies or bioactive mediators, yet underlying mechanisms are incompletely understood. Sphingolipids such as ceramide regulate lung injury, and their composition changes as a function of time in stored blood. Here, we tested the hypothesis that aged platelets may induce lung injury via a sphingolipid-mediated mechanism. To assess this hypothesis, a two-hit mouse model was devised. Recipient mice were treated with 2 mg/kg intraperitoneal lipopolysaccharide (priming) 2 h before transfusion of 10 ml/kg stored (1–5 days) platelets treated with or without addition of acid sphingomyelinase inhibitor ARC39 or platelets from acid sphingomyelinase-deficient mice, which both reduce ceramide formation. Transfused mice were examined for signs of pulmonary neutrophil accumulation, endothelial barrier dysfunction, and histological evidence of lung injury. Sphingolipid profiles in stored platelets were analyzed by mass spectrophotometry. Transfusion of aged platelets into primed mice induced characteristic features of lung injury, which increased in severity as a function of storage time. Ceramide accumulated in platelets during storage, but this was attenuated by ARC39 or in acid sphingomyelinase-deficient platelets. Compared with wild-type platelets, transfusion of ARC39-treated or acid sphingomyelinase-deficient aged platelets alleviated lung injury. Aged platelets elicit lung injury in primed recipient mice, which can be alleviated by pharmacological inhibition or genetic deletion of acid sphingomyelinase. Interventions targeting sphingolipid formation represent a promising strategy to increase the safety and longevity of stored blood products.

Download Full-text

Modulation of endoperoxide product levels and cyclophosphamide-induced injury by glutathione repletion

Journal of Applied Physiology ◽

10.1152/jappl.1989.67.6.2316 ◽

1989 ◽

Vol 67 (6) ◽

pp. 2316-2322 ◽

Cited By ~ 12

Author(s):

J. A. Cooper ◽

W. W. Merrill

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Bronchoalveolar Lavage ◽

Arachidonic Acid Metabolism ◽

Glutathione Depletion ◽

Enzymatic Reactions ◽

Variable Degree ◽

Cyclophosphamide Treatment ◽

Dose Dependent

Glutathione is a tripeptide important in a number of diverse cellular functions including enzymatic reactions involved in prostaglandin endoperoxide metabolism. We have previously reported that cyclophosphamide administration to rats results in acute lung injury manifested by increased bronchoalveolar lavage albumin concentrations. In the current study we examine whether cyclophosphamide treatment affects pulmonary glutathione stores or bronchoalveolar endoperoxide metabolic product levels and whether these effects may be related to acute lung injury caused by the drug. We show that cyclophosphamide treatment causes a dose-dependent reduction in pulmonary glutathione stores 4 h after drug administration. In addition, acute lung injury as the result of cyclophosphamide can be abrogated by coadministration of oxothiazolidine carboxylate, an intracellular cysteine delivery system that also reverses pulmonary glutathione depletion induced by cyclophosphamide in our study. Finally, cyclophosphamide treatment reduces prostaglandin E2 concentrations in bronchoalveolar lavage and alveolar macrophage culture supernatant in a dose-dependent fashion and increases bronchoalveolar thromboxane concentrations in low dose-treated animals. These effects are reversed to a variable degree by coadministration of oxothiazolidine carboxylate. Our study suggests in vivo pulmonary arachidonic acid metabolism and cyclophosphamide-induced acute lung injury are modulated by cellular glutathione stores. These findings may have important implications for the treatment of acute lung injury.

Download Full-text

Dimethyl Fumarate Ameliorates Lipopolysaccharide-induced Acute Lung Injury by Inhibiting NLRP3 Inflammasome-mediated Pyroptosis

10.21203/rs.3.rs-626638/v1 ◽

2021 ◽

Author(s):

Huayu Li ◽

Mengyan Li ◽

Chao Dong ◽

Bing Liu

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Nlrp3 Inflammasome ◽

Therapeutic Potential ◽

Critical Role ◽

Specific Effect ◽

Dimethyl Fumarate ◽

Related Factor ◽

Pyrin Domain ◽

Anti Inflammatory

Abstract Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders, and there are currently no Food and Drug Administration-approved drug therapies. It is established that Dimethyl fumarate (DMF) exhibits anti inflammatory effects, however, the specific effect of DMF on ALI remains largely unknown. The aim of the present study was to investigate whether, and by which mechanism, DMF alleviated lipopolysaccharide (LPS)-induced ALI. We found that intraperitoneal injection of DMF markedly reduced the pulmonary injury, decreased pulmonary edema and pulmonary permeability. Emerging studies suggested that the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis played a critical role during ALI. NLRP3 inflammasome-mediated pyroptosis is significantly activated with the cleavage of caspase-1 and GSDMD occurring in the lung of LPS-induced ALI. DMF inhibited the activation of the NLRP3 inflammasome and pyroptosis in both lung of ALI mice and LPS-induced BEAS-2B cells. Mechanistically, DMF enhanced expressions of Nuclear factor erythroid-2-related factor 2 (Nrf2), leading to inactivation of NLRP3 inflammasome and reduction of pyroptosis in both ALI mice and LPS-induced BEAS-2B cells. Conversely, Nrf2 inhibitor reduced the inhibitory effects of DMF on NLRP3 inflammasome and pyroptosis, and consequently blocked the improvement roles of DMF on ALI in mice. This study for the first time demonstrated that DMF could improve LPS-induced ALI via inhibiting NLRP3 inflammasome and pyroptosis, and that these effects were mediated by triggering Nrf2 expression, suggesting a therapeutic potential of DMF as an anti-inflammatory agent for ALI/ARDS treatment.

Download Full-text

Inhalable Jojoba Oil Dry Nanoemulsion Powders for the Treatment of Lipopolysaccharide- or H2O2-Induced Acute Lung Injury

Pharmaceutics ◽

10.3390/pharmaceutics13040486 ◽

2021 ◽

Vol 13 (4) ◽

pp. 486

Author(s):

Guoli Zhang ◽

Fei Xie ◽

Yunbo Sun ◽

Xiang Yu ◽

Zhimei Xiao ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Caspase 3 ◽

Lipid Peroxide ◽

Skin Barrier ◽

Inflammatory Cells ◽

Immunohistochemical Method ◽

Total Protein Content ◽

Jojoba Oil ◽

Anti Inflammatory

Jojoba (Simmondsia chinensis (Link) C.K. Schneid) is a dioecious plant in desert and semi-desert areas, e.g., the Ismailia Desert in Egypt. Jojoba oil (JJBO) is a natural slight yellow oil with the functions of skin barrier repairing and wound healing, which is dermally applied as a traditional medication or cosmetic in the Middle East. The objective of this study was to prepare JJBO dry nanoemulsion powders (JNDs) and investigate their anti-acute lung injury effects. JJBO nanoemulsions (JNEs) were prepared and then lyophilized to JNDs and the properties and simulated lung deposition were measured. Rat acute lung injury (ALI) models were established after intratracheal (i.t.) administration of lipopolysaccharide (LPS) or hydrogen peroxide (H2O2). JNDs and dexamethasone (DXM) solutions were also i.t. administered to the rats. The pathological states of lung tissues were checked. Inflammatory and oxidative factors in the lung tissues were determined using ELISA methods. NF-κB p65 and caspase-3 were measured with a Western blotting method and an immunohistochemical method, respectively. JNDs had an appropriate mass median aerodynamic diameter (MMAD) of 4.17 µm and a fine particle fraction (FPF) of 39.11%. JNDs showed higher anti-inflammatory effect on LPS-induced ALI than DXM with a decrease in total protein content and down-regulation of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and NF-κB p65. JNDs also showed higher anti-inflammatory and anti-oxidation effect on H2O2-induced ALI than DXM with elimination of reactive oxygen species (ROS), increasing of superoxide dismutase (SOD), decrease in of lipid peroxide malondialdehyde (MDA) and glutathione (GSH), and inhibition of caspase-3 expression. Moreover, i.t. JNDs attenuated bleeding and infiltrations of the inflammatory cells in the two ALI models. JNDs are a promising natural oil-contained inhalable medication for the treatment of LPS- or H2O2-induced ALI.

Download Full-text

Bigelovii A Protects against Lipopolysaccharide-Induced Acute Lung Injury by Blocking NF-κB and CCAAT/Enhancer-Binding ProteinδPathways

Mediators of Inflammation ◽

10.1155/2016/9201604 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Chunguang Yan ◽

Fuqin Guan ◽

Yanfei Shen ◽

Huifang Tang ◽

Dong Yuan ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

P38 Mapk ◽

Inflammatory Mediators ◽

Neutrophil Infiltration ◽

Therapeutic Approaches ◽

Lps Challenge ◽

Enhancer Binding Protein ◽

Underlying Mechanisms

Optimal methods are applied to acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), but the mortality rate is still high. Accordingly, further studies dedicated to identify novel therapeutic approaches to ALI are urgently needed. Bigelovii A is a new natural product and may exhibit anti-inflammatory activity. Therefore, we sought to investigate its effect on lipopolysaccharide- (LPS-) induced ALI and the underlying mechanisms. We found that LPS-induced ALI was significantly alleviated by Bigelovii A treatment, characterized by reduction of proinflammatory mediator production, neutrophil infiltration, and lung permeability. Furthermore, Bigelovii A also downregulated LPS-stimulated inflammatory mediator expressionsin vitro. Moreover, both NF-κB and CCAAT/enhancer-binding proteinδ(C/EBPδ) activation were obviously attenuated by Bigelovii A treatment. Additionally, phosphorylation of both p38 MAPK and ERK1/2 (upstream signals of C/EBPδactivation) in response to LPS challenge was also inhibited by Bigelovii A. Therefore, Bigelovii A could attenuate LPS-induced inflammation by suppression of NF-κB, inflammatory mediators, and p38 MAPK/ERK1/2—C/EBPδ, inflammatory mediators signaling pathways, which provide a novel theoretical basis for the possible application of Bigelovii A in clinic.

Download Full-text

Protective Effect of the Fruit Hull ofGleditsia sinensison LPS-Induced Acute Lung Injury Is Associated with Nrf2 Activation

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/974713 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 12

Author(s):

Jun-Young Choi ◽

Min Jung Kwun ◽

Kyun Ha Kim ◽

Ji Hyo Lyu ◽

Chang Woo Han ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Lung Inflammation ◽

Therapeutic Option ◽

Raw 264.7 Cells ◽

Inflammatory Factor ◽

Tnf Α ◽

Reporter Assays ◽

Anti Inflammatory ◽

Underlying Mechanisms

The fruit hull ofGleditsia sinensis(FGS) has been prescribed as a traditional eastern Asian medicinal remedy for the treatment of various respiratory diseases, but the efficacy and underlying mechanisms remain poorly characterized. Here, we explored a potential usage of FGS for the treatment of acute lung injury (ALI), a highly fatal inflammatory lung disease that urgently needs effective therapeutics, and investigated a mechanism for the anti-inflammatory activity of FGS. Pretreatment of C57BL/6 mice with FGS significantly attenuated LPS-induced neutrophilic lung inflammation compared to sham-treated, inflamed mice. Reporter assays, semiquantitative RT-PCR, and Western blot analyses show that while not affecting NF-κB, FGS activated Nrf2 and expressed Nrf2-regulated genes including GCLC, NQO-1, and HO-1 in RAW 264.7 cells. Furthermore, pretreatment of mice with FGS enhanced the expression of GCLC and HO-1 but suppressed that of proinflammatory cytokines in including TNF-α and IL-1β in the inflamed lungs. These results suggest that FGS effectively suppresses neutrophilic lung inflammation, which can be associated with, at least in part, FGS-activating anti-inflammatory factor Nrf2. Our results suggest that FGS can be developed as a therapeutic option for the treatment of ALI.

Download Full-text

Icariside II regulates TLR4/NF-κB signaling pathway to improve septic lung injury

10.22514/sv.2021.216 ◽

2021 ◽

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

High Mortality ◽

Biological Activities ◽

Flavonoid Compound ◽

Therapeutic Drug ◽

Inadequate Response ◽

Mice Model ◽

Stress Injury ◽

Icariside Ii

Sepsis is caused by the inadequate response to infection and may eventually lead to fatal organ dysfunction and a high mortality rate. Acute lung injury (ALI) caused by sepsis is an important cause of its high mortality, so effective treatment drugs are urgently needed. Icariside II (ICA II) is derived from Epimedii, a ubiquitous biological flavonoid compound. ICA II has shown multiple biological activities. ICA II alleviates LPS-induced neuroinflammation by inhibiting the TLR4 / MyD88 /NF-κB pathway, however, the possible role of icaridinin II in sepsis induced acute lung injury remains unclear. Herein, we developed a sepsis-related ALI mice model induced by LPS treatment, and found Icariside II ameliorated sepsis-related acute lung injury of mice induced by LPS. Our data further confirmed that Icariside II inhibited the inflammatory response in sepsis-related ALI mice, and ameliorated oxidative stress injury. We further revealed Icariside II inhibited the apoptosis of lung cells via TLR4-NF-κB axis. Our data therefore provided a promising therapeutic drug for the treatment of sepsis-induced ALI.

Download Full-text