scholarly journals Terretonin as a New Protective Agent against Sepsis-Induced Acute Lung Injury: Impact on SIRT1/Nrf2/NF-κBp65/NLRP3 Signaling

Biology ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1219
Author(s):  
Gamal A. Mohamed ◽  
Sabrin R. M. Ibrahim ◽  
Dina S. El-Agamy ◽  
Wael M. Elsaed ◽  
Alaa Sirwi ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Nuclear Factor Κb ◽  
Protein Carbonyl ◽  
Lung Damage ◽  
Protective Agent ◽  
Protective Effects ◽  
Apoptotic Marker ◽  
Tetracyclic Core ◽  
Factor Α

Endophytic fungi are proving to be an excellent source of chemical entities with unique structures and varied bioactivities. Terretonin (TE) and its structurally related derivatives are a class of meroterpenoids, possessing the same unique tetracyclic core skeleton, which have been reported from the Aspergillus genus. This study was carried out to assess the potential protective effects of TE separated from the endophytic fungus A. terreus against LPS (lipopolysaccharide)-induced ALI (acute lung injury) in mice. The results revealed that TE alleviated pulmonary edema as it lowered both the W/D lung ratio and protein content. The inflammatory response represented by inflammatory cell infiltration into the lung tissues was greatly repressed by TE. That was supported by the improved histopathological results and also by the reduced level of myeloperoxidase in the lung. TE showed a potent antioxidant activity as it attenuated lipid peroxidative markers (malondialdehyde, 4-hydroxynonenal, and protein carbonyl) and enhanced endogenous antioxidants (reduced glutathione, superoxide dismutase, and catalase) in lung tissues. Similarly, TE increased the mRNA expression of SIRT1, Nrf2, and its genes (HO-1, NQO1, and GCLm). On the other hand, TE restrained the activation of NF-κB (nuclear factor-κB) in the lung. Consequently, TE depressed the pro-inflammatory cytokines: nitric oxide (NOx), TNF-α (tumor necrosis factor-α), and interleukins (IL-6 and -1β). Additionally, TE inhibited NLRP3 signaling and interrupted apoptosis by decreasing the levels of proapoptotic markers (Bax and caspase-3) and increasing the level of an anti-apoptotic marker (Bcl-2). In conclusion, TE had a remarkable protective potential on LPS-induced lung damage via antioxidant and anti-inflammatory mechanisms. This finding encourages further investigations on this promising candidate.

6-Gingerol Ameliorates Sepsis Induced Acute Lung Injury by Regulating Nuclear Factor-κB and Nuclear-Factor Erythroid 2-Related Factor 2/Heme Oxygenase-1 Signaling Pathways

2020 ◽  
Vol 19 (3) ◽  
pp. 255-260
Author(s):  
Fan Yang ◽  
Lu Deng ◽  
MuHu Chen ◽  
Ying Liu ◽  
Jianpeng Zheng
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Heme Oxygenase ◽  
Interleukin 1 ◽  
Nuclear Factor Κb ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Alveolar Collapse ◽  
Factor Α

Acute lung injury initiated systemic inflammation leads to sepsis. Septic mice show a series of degenerative changes in lungs as demonstrated by pulmonary congestion, alveolar collapse, inflammatory cell infiltration, and increased wet-todry weight in lungs. 6-Gingerol ameliorates histopathological changes and clinical outcome of the sepsis. The increase in the levels of tumor necrosis factor-α, interleukin-1 beta, interleukin-6, and interleukin-18 in septic mice were reduced by administration with 6-Gingerol. Also, 6-Gingerol attenuates sepsis-induced increase of malonaldehyde and decrease of catalase, superoxide, and glutathione. Enhanced phospho-p65, reduced nuclear factor erythropoietin-2-related factor 2, and heme oxygenase 1 in septic mice were reversed by administration with 6-Gingerol. In conclusion, 6-Gingerol demonstrates anti-inflammatory and antioxidant effects against sepsis associated acute lung injury through inactivation of nuclear factor-kappa B and activation of nuclear-factor erythroid 2-related factor 2 pathways.

Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury

2000 ◽  
Vol 279 (6) ◽  
pp. L1137-L1145 ◽  
Author(s):  
Edward Abraham ◽  
Aaron Carmody ◽  
Robert Shenkar ◽  
John Arcaroli
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Lung Edema ◽  
Protein Levels ◽  
Inflammatory Protein ◽  
Transcriptional Regulatory ◽  
Tnf Α ◽  
Factor Α

Acute lung injury is characterized by accumulation of neutrophils in the lungs, accompanied by the development of interstitial edema and an intense inflammatory response. To assess the role of neutrophils as early immune effectors in hemorrhage- or endotoxemia-induced lung injury, mice were made neutropenic with cyclophosphamide or anti-neutrophil antibodies. Endotoxemia- or hemorrhage-induced lung edema was significantly reduced in neutropenic animals. Activation of the transcriptional regulatory factor nuclear factor-κB after hemorrhage or endotoxemia was diminished in the lungs of neutropenic mice compared with nonneutropenic controls. Hemorrhage or endotoxemia was followed by increases in pulmonary mRNA and protein levels for interleukin-1β (IL-1β), macrophage inflammatory protein-2 (MIP-2), and tumor necrosis factor-α (TNF-α). Endotoxin-induced increases in proinflammatory cytokine expression were greater than those found after hemorrhage. The amounts of mRNA or protein for IL-1β, MIP-2, and TNF-α were significantly lower after hemorrhage in the lungs of neutropenic versus nonneutropenic mice. Neutropenia was associated with significant reductions in IL-1β and MIP-2 but not in TNF-α expression in the lungs after endotoxemia. These experiments show that neutrophils play a centrol role in initiating acute inflammatory responses and causing injury in the lungs after hemorrhage or endotoxemia.

Topiroxostat ameliorates oxidative stress and inflammation in sepsis-induced lung injury

2020 ◽  
Vol 75 (11-12) ◽  
pp. 425-431
Author(s):  
Haiying Fu ◽  
Junjie Zhang ◽  
Mayu Huang
Keyword(s):  
Oxidative Stress ◽  
Lung Injury ◽  
Vital Role ◽  
Lung Damage ◽  
Enzyme Linked Immunosorbent Assay ◽  
Protective Effects ◽  
Chemotactic Protein ◽  
Apoptosis Protein ◽  
Factor Α ◽  
Related Proteins

AbstractSepsis-induced lung injury was the most common cause of death in patients. Topiroxostat, a novel xanthine oxidoreductase inhibitors, possessed obvious organ protectives effects. Xanthine oxidase played a vital role in acute lung injury. The study aimed to investigate the roles of Topiroxostat in sepsis-induced lung injury. The sepsis rats were established using cecum ligation and perforation. The lung damage induced by sepsis was evaluated by Hematoxylin and Eosin staining and lung tissue wet to dry ratio. The oxidative stress was detected by measurement of reactive oxygen species, malondialdehyde, myeloperoxidase and superoxide dismutase (SOD). The pro-inflammatory mediators, tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and monocyte chemotactic protein 1, were measured by Enzyme-Linked Immunosorbent Assay. The cell apoptosis in lung was detected by TUNNEL staining and western blot analysis of apoptosis-related proteins including pro-apoptosis proteins, Bax, cleaved caspase9, cleaved caspase3 and anti-apoptosis protein Bcl2. The results showed that Topiroxostat significantly reduced lung damage, along with decreased oxidative stress, inflammation response and apoptosis in sepsis rats. Topiroxostat exerted markedly protective effects in sepsis-induced lung injury and could be an antioxidant in treating sepsis-induced lung injury.

scholarly journals Sodium Thiosulfate Attenuates Acute Lung Injury in Mice

2014 ◽  
Vol 121 (6) ◽  
pp. 1248-1257 ◽  
Author(s):  
Masahiro Sakaguchi ◽  
Eizo Marutani ◽  
Hae-sook Shin ◽  
Wei Chen ◽  
Kenjiro Hanaoka ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Acute Lung Injury ◽  
Tumor Necrosis Factor ◽  
Lung Injury ◽  
Tumor Necrosis ◽  
Cecal Ligation ◽  
Sodium Thiosulfate ◽  
Nuclear Factor Κb ◽  
Factor Α ◽  
Necrosis Factor

Abstract Background: Acute lung injury is characterized by neutrophilic inflammation and increased lung permeability. Thiosulfate is a stable metabolite of hydrogen sulfide, a gaseous mediator that exerts antiinflammatory effects. Although sodium thiosulfate (STS) has been used as an antidote, the effect of STS on acute lung injury is unknown. The authors assessed the effects of STS on mice lung and vascular endothelial cells subjected to acute inflammation. Methods: Lung injury was assessed in mice challenged with intratracheal lipopolysaccharide or subjected to cecal ligation and puncture with or without STS. Effects of STS on endothelial permeability and the production of inflammatory cytokines and reactive oxygen species were examined in cultured endothelial cells incubated with lipopolysaccharide or tumor necrosis factor-α. Levels of sulfide and sulfane sulfur were measured using novel fluorescence probes. Results: STS inhibited lipopolysaccharide-induced production of cytokines (interleukin-6 [pg/ml]; 313 ± 164, lipopolysaccharide; 79 ± 27, lipopolysaccharide + STS [n = 10]), lung permeability, histologic lung injury, and nuclear factor-κB activation in the lung. STS also prevented up-regulation of interleukin-6 in the mouse lung subjected to cecal ligation and puncture. In endothelial cells, STS increased intracellular levels of sulfide and sulfane sulfur and inhibited lipopolysaccharide or tumor necrosis factor-α–induced production of cytokines and reactive oxygen species. The beneficial effects of STS were associated with attenuation of the lipopolysaccharide-induced nuclear factor-κB activation through the inhibition of tumor necrosis factor receptor–associated factor 6 ubiquitination. Conclusions: STS exerts robust antiinflammatory effects in mice lung and vascular endothelium. The results suggest a therapeutic potential of STS in acute lung injury.

scholarly journals Protectin conjugates in tissue regeneration 1 restores lipopolysaccharide-induced pulmonary endothelial glycocalyx loss via ALX/SIRT1/NF-kappa B axis

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xin-Yang Wang ◽  
Xin-Yu Li ◽  
Cheng-Hua Wu ◽  
Yu Hao ◽  
Pan-Han Fu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Cytokines ◽  
Tissue Regeneration ◽  
Umbilical Vein ◽  
Endothelial Glycocalyx ◽  
Lipid Mediator ◽  
Protective Effects ◽  
Pulmonary Vascular Permeability

Abstract Background Endothelial glycocalyx loss is integral to increased pulmonary vascular permeability in sepsis-related acute lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is a novel macrophage-derived lipid mediator exhibiting potential anti-inflammatory and pro-resolving benefits. Methods PCTR1 was administrated intraperitoneally with 100 ng/mouse after lipopolysaccharide (LPS) challenged. Survival rate and lung function were used to evaluate the protective effects of PCTR1. Lung inflammation response was observed by morphology and inflammatory cytokines level. Endothelial glycocalyx and its related key enzymes were measured by immunofluorescence, ELISA, and Western blot. Afterward, related-pathways inhibitors were used to identify the mechanism of endothelial glycocalyx response to PCTR1 in mice and human umbilical vein endothelial cells (HUVECs) after LPS administration. Results In vivo, we show that PCTR1 protects mice against lipopolysaccharide (LPS)-induced sepsis, as shown by enhanced the survival and pulmonary function, decreased the inflammatory response in lungs and peripheral levels of inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β. Moreover, PCTR1 restored lung vascular glycocalyx and reduced serum heparin sulphate (HS), syndecan-1 (SDC-1), and hyaluronic acid (HA) levels. Furthermore, we found that PCTR1 downregulated heparanase (HPA) expression to inhibit glycocalyx degradation and upregulated exostosin-1 (EXT-1) protein expression to promote glycocalyx reconstitution. Besides, we observed that BAY11-7082 blocked glycocalyx loss induced by LPS in vivo and in vitro, and BOC-2 (ALX antagonist) or EX527 (SIRT1 inhibitor) abolished the restoration of HS in response to PCTR1. Conclusion PCTR1 protects endothelial glycocalyx via ALX receptor by regulating SIRT1/NF-κB pathway, suggesting PCTR1 may be a significant therapeutic target for sepsis-related acute lung injury.

Protective effects of coumestrol on lipopolysaccharide-induced acute lung injury via the inhibition of proinflammatory mediators and NF-κB activation

2017 ◽  
Vol 34 ◽  
pp. 181-188 ◽  
Author(s):  
Heung Joo Yuk ◽  
Jae Won Lee ◽  
Hyun Ah Park ◽  
Ok-Kyoung Kwon ◽  
Kyeong-Hwa Seo ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Protective Effects ◽  
Proinflammatory Mediators

Class B Scavenger Receptors BI and BII Protect Against LPS-induced Acute Lung Injury in Mice by Mediating LPS Clearance

2021 ◽  
Author(s):  
Irina N. Baranova ◽  
Alexander V. Bocharov ◽  
Tatyana G. Vishnyakova ◽  
Zhigang Chen ◽  
Anna A. Birukova ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Transgenic Mice ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Protective Role ◽  
Lung Damage ◽  
Wild Type ◽  
Class B ◽  
Anti Inflammatory

Recent studies suggest an anti-inflammatory protective role for class B scavenger receptor BI (SR-BI) in endotoxin-induced inflammation and sepsis. Other data, including ours, provide evidence for an alternative role of SR-BI, facilitating bacterial and endotoxin uptake, and contributing to inflammation and bacterial infection. Enhanced endotoxin susceptibility of SR-BI deficient mice due to their anti-inflammatory glucocorticoid deficiency complicates understanding SR-BI’s role in endotoxemia/sepsis, calling for use of alternative models. In this study, using hSR-BI and hSR-BII transgenic mice, we found that SR-BI and to a lesser extent its splicing variant SR-BII, protects against LPS-induced lung damage. At 20 hours after intratracheal LPS instillation the extent of pulmonary inflammation and vascular leakage was significantly lower in hSR-BI and hSR-BII transgenic mice compared to wild type mice. Higher bronchoalveolar lavage fluid (BALF) inflammatory cell count and protein content as well as lung tissue neutrophil infiltration found in wild type mice was associated with markedly (2-3 times) increased pro-inflammatory cytokine production as compared to transgenic mice following LPS administration. Markedly lower endotoxin levels detected in BALF of transgenic vs. wild type mice along with the significantly increased BODIPY-LPS uptake observed in lungs of hSR-BI and hSR-BII mice 20 hours after the IT LPS injection suggest that hSR-BI and hSR-BII-mediated enhanced LPS clearance in the airways could represent the mechanism of their protective role against LPS-induced acute lung injury.

scholarly journals Garcinia Multiflora Inhibits FPR1-Mediated Neutrophil Activation and Protects Against Acute Lung Injury

2018 ◽  
Vol 51 (6) ◽  
pp. 2776-2793 ◽  
Author(s):  
Yung-Fong Tsai ◽  
Shun-Chin Yang ◽  
Wen-Yi Chang ◽  
Jih-Jung Chen ◽  
Chun-Yu Chen ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Superoxide Anion ◽  
Calcium Influx ◽  
Neutrophil Activation ◽  
Lung Damage ◽  
Hek293 Cells ◽  
Human Neutrophils ◽  
Therapeutic Effects

Background/Aims: Formyl peptide receptors (FPRs) recognize different endogenous and exogenous molecular stimuli and mediate neutrophil activation. Dysregulation of excessive neutrophil activation and the resulting immune responses can induce acute lung injury (ALI) in the host. Accordingly, one promising approach to the treatment of neutrophil-dominated inflammatory diseases involves therapeutic FPR1 inhibition. Methods: We extracted a potent FPR1 antagonist from Garcinia multiflora Champ. (GMC). The inhibitory effects of GMC on superoxide anion release and elastase degranulation from activated human neutrophils were determined with spectrophotometric analysis. Reactive oxygen species (ROS) production and the FPR1 binding ability of neutrophils were assayed by flow cytometry. Signaling transduction mediated by GMC in response to chemoattractants was assessed with a calcium influx assay and western blotting. A lipopolysaccharide (LPS)-induced ALI mouse model was used to determine the therapeutic effects of GMC in vivo. Results: GMC significantly reduced superoxide anion release, the reactive oxidants derived therefrom, and elastase degranulation mediated through selective, competitive FPR1 blocking in N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLF)-stimulated human neutrophils. In cell-free systems, GMC was unable to scavenge superoxide anions or suppress elastase activity. GMC produced a right shift in fMLF-activated concentration-response curves and was confirmed to be a competitive FPR1 antagonist. GMC binds to FPR1 not only in neutrophils, but also FPR1 in neutrophil-like THP-1 and hFPR1-transfected HEK293 cells. Furthermore, the mobilization of calcium and phosphorylation of mitogen-activated protein kinases and Akt, which are involved in FPR1-mediated downstream signaling, was competitively blocked by GMC. In an in vivo study, GMC significantly reduced pulmonary edema, neutrophil infiltration, and alveolar damage in LPS-induced ALI mice. Conclusion: Our findings demonstrate that GMC is a natural competitive FPR1 inhibitor, which makes it a possible anti-inflammatory treatment option for patients critically inflicted with FPR1-mediated neutrophilic lung damage.

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