scholarly journals β-Nitrostyrene derivatives attenuate LPS-mediated acute lung injury via the inhibition of neutrophil-platelet interactions and NET release

2018 ◽  
Vol 314 (4) ◽  
pp. L654-L669 ◽  
Author(s):  
Yao-Wen Chang ◽  
Ching-Ping Tseng ◽  
Chih-Hsun Lee ◽  
Tsong-Long Hwang ◽  
Yu-Li Chen ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Diseases ◽  
Treatment Strategies ◽  
Neutrophil Function ◽  
Neutrophil Extracellular Trap ◽  
Myeloperoxidase Activity ◽  
Protective Effects ◽  
Neutrophil Accumulation ◽  
Net Release

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are high-mortality and life-threatening diseases that are associated with neutrophil activation and accumulation within lung tissue. Emerging evidence indicates that neutrophil-platelet aggregates (NPAs) at sites of injury increase acute inflammation and contribute to the development of ALI. Although numerous studies have increased our understanding of the pathophysiology of ALI, there is still a lack of innovative and useful treatments that reduce mortality, emphasizing that there is an urgent need for novel treatment strategies. In this study, a new series of small compounds of β-nitrostyrene derivatives (BNSDs) were synthesized, and their anti-inflammatory bioactivities on neutrophils and platelets were evaluated. The new small compound C7 modulates neutrophil function by inhibiting superoxide generation and elastase release. Compound C7 elicits protective effects on LPS-induced paw edema and acute lung injury via the inhibition of neutrophil accumulation, proinflammatory mediator release, platelet aggregation, myeloperoxidase activity, and neutrophil extracellular trap (NET) release. NET formation was identified as the bridge for the critical interactions between neutrophils and platelets by confocal microscopy and flow cytometry. This research provides new insights for elucidating the complicated regulation of neutrophils and platelets in ALI and sheds further light on future drug development strategies for ALI/ARDS and acute inflammatory diseases.

scholarly journals Ganoderic acid A attenuates lipopolysaccharide-induced lung injury in mice

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Bing Wan ◽  
Yan Li ◽  
Shuangshuang Sun ◽  
Yang Yang ◽  
Yanling LV ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Model ◽  
Weight Ratio ◽  
Dry Weight ◽  
Lavage Fluid ◽  
Myeloperoxidase Activity ◽  
Protective Effects ◽  
Ganoderic Acid ◽  
Lower Lung

Abstract The present study aimed to investigate the protective effects of ganoderic acid A (GAA) on lipopolysaccharide (LPS)-induced acute lung injury. In mouse model of LPS-induced acute lung injury, we found that GAA led to significantly lower lung wet-to-dry weight ratio and lung myeloperoxidase activity, and attenuated pathological damages. In addition, GAA increased superoxide dismutase activity, but decreased malondialdehyde content and proinflammatory cytokines levels in the bronchoalveolar lavage fluid. Mechanistically, GAA reduced the activation of Rho/ROCK/NF-κB pathway to inhibit LPS-induced inflammation. In conclusion, our study suggests that GAA attenuates acute lung injury in mouse model via the inhibition of Rho/ROCK/NF-κB pathway.

scholarly journals GPA Peptide Attenuates Sepsis-Induced Acute Lung Injury in Mice via Inhibiting Oxidative Stress and Pyroptosis of Alveolar Macrophage

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Yukun Liu ◽  
Yongsheng Zhang ◽  
Quanrui Feng ◽  
Qinxin Liu ◽  
Jie Xie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Alveolar Macrophage ◽  
Inflammatory Cell ◽  
Tissue Injury ◽  
Inflammatory Diseases ◽  
Cecal Ligation ◽  
Regulatory Function ◽  
Protective Effects

Acute lung injury (ALI) has been known to be a devastating form of respiratory infection and an important contributor to mortality in intensive care, due to its lacking of effective treatment. Inflammation, oxidative stress, and pyroptosis are associated with multiple kinds of inflammatory diseases such as ALI. It is commonly accepted that Gly-Pro-Ala (GPA) peptide regulates oxidative stress and pyroptosis in different kinds of inflammatory diseases. Our study is aimed at exploring the regulatory function and protective effects of GPA peptides on ALI. In the current study, the cecal ligation and puncture (CLP) technique was used to evoke sepsis in mice, and GPA peptide was administered intraperitoneally with different concentrations (50, 100, and 150 mg/kg) after CLP. Histopathological changes and the ratio of wet-to-dry in lung were recorded and analyzed. We also investigated the level of oxidative stress, inflammation, and pyroptosis. Results showed that GPA peptide significantly ameliorated CLP-stimulated lung tissue injury, impeded proinflammatory cytokine release, and reduced inflammatory cell infiltration. Additionally, GPA peptide suppressed oxidative stress and caspase-1-dependent pyroptosis in alveolar macrophages. Furthermore, our study showed that the GPA peptide prevents alveolar macrophage from undergoing pyroptosis by attenuating ROS. In conclusion, results demonstrated that GPA peptide has protective effects in CLP-stimulated ALI by inhibiting oxidative stress as well as pyroptosis of alveolar macrophage.

scholarly journals Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury

2008 ◽  
Vol 295 (3) ◽  
pp. L497-L504 ◽  
Author(s):  
Xia Zhao ◽  
Jaroslaw W. Zmijewski ◽  
Emmanuel Lorne ◽  
Gang Liu ◽  
Young-Jun Park ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Nuclear Translocation ◽  
Lavage Fluid ◽  
Neutrophil Function ◽  
Neutrophil Activation ◽  
Neutrophil Accumulation ◽  
Murine Bone Marrow ◽  
Interstitial Pulmonary Edema ◽  
Tnf Α

AMP-activated protein kinase (AMPK) is activated by increases in the intracellular AMP-to-ATP ratio and plays a central role in cellular responses to metabolic stress. Although activation of AMPK has been shown to have anti-inflammatory effects, there is little information concerning the role that AMPK may play in modulating neutrophil function and neutrophil-dependent inflammatory events, such as acute lung injury. To examine these issues, we determined the effects of pharmacological activators of AMPK, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) and barberine, on Toll-like receptor 4 (TLR4)-induced neutrophil activation. AICAR and barberine dose-dependently activated AMPK in murine bone marrow neutrophils. Exposure of LPS-stimulated neutrophils to AICAR or barberine inhibited release of TNF-α and IL-6, as well as degradation of IκBα and nuclear translocation of NF-κB, compared with findings in neutrophil cultures that contained LPS without AICAR or barberine. Administration of AICAR to mice resulted in activation of AMPK in the lungs and was associated with decreased severity of LPS-induced lung injury, as determined by diminished neutrophil accumulation in the lungs, reduced interstitial pulmonary edema, and diminished levels of TNF-α and IL-6 in bronchoalveolar lavage fluid. These results suggest that AMPK activation reduces TLR4-induced neutrophil activation and diminishes the severity of neutrophil-driven proinflammatory processes, including acute lung injury.

Partial liquid ventilation protects lung during resuscitation from shock

1997 ◽  
Vol 83 (5) ◽  
pp. 1666-1670 ◽  
Author(s):  
John G. Younger ◽  
Ali S. Taqi ◽  
Gerd O. Till ◽  
Ronald B. Hirschl
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Capillary Permeability ◽  
Myeloperoxidase Activity ◽  
Partial Liquid Ventilation ◽  
Capillary Leak ◽  
Permeability Index ◽  
Neutrophil Accumulation ◽  
Liquid Ventilation ◽  
Strong Trend

Younger, John G., Ali S. Taqi, Gerd O. Till, and Ronald B. Hirschl. Partial liquid ventilation protects lung during resuscitation from shock. J. Appl. Physiol. 83(5): 1666–1670, 1997.—Preliminary animal experience with partial liquid ventilation (PLV) suggests that this therapy may diminish neutrophil invasion and capillary leak during acute lung injury. We sought to confirm these findings in a model of shock-induced lung injury. Sixty anesthetized rats were studied. After hemorrhage to an arterial pressure of 25 mmHg for 45 min, animals were resuscitated with blood and saline and treated with gas ventilation alone or with 5 ml/kg of intratracheally administered perflubron. Myeloperoxidase activity was used to measure lung neutrophil content. A permeability index (the bronchoalveolar-to-blood ratio of125I-labeled albumin activity) quantified alveolar leak. Injury caused an increase in myeloperoxidase that was reversed by PLV (injury = 0.837 ± 0.452, PLV = 0.257 ± 0.165; P < 0.01). Capillary permeability also increased with hemorrhage, with a strong trend toward improvement in the PLV group (permeability indexes: injury = 0.094 ± 0.102, PLV = 0.045 ± 0.045; 95% confidence interval for injury − PLV: −0.024, 0.1219). We conclude that PLV is associated with a decrease in pulmonary neutrophil accumulation and a trend toward decreased capillary leak after hemorrhagic shock.

scholarly journals Dopamine inhibits pulmonary edema through the VEGF-VEGFR2 axis in a murine model of acute lung injury

2012 ◽  
Vol 302 (2) ◽  
pp. L185-L192 ◽  
Author(s):  
Pawan K. Vohra ◽  
Luke H. Hoeppner ◽  
Gunisha Sagar ◽  
Shamit K. Dutta ◽  
Sanjay Misra ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Pulmonary Edema ◽  
Vascular Permeability ◽  
Murine Model ◽  
Therapeutic Effects ◽  
Myeloperoxidase Activity ◽  
Protective Effects ◽  
Vascular Permeability Factor ◽  
Edema Formation

The neurotransmitter dopamine and its dopamine receptor D2 (D2DR) agonists are known to inhibit vascular permeability factor/vascular endothelial growth factor (VEGF)-mediated angiogenesis and vascular permeability. Lung injury is a clinical syndrome associated with increased microvascular permeability. However, the effects of dopamine on pulmonary edema, a phenomenon critical to the pathophysiology of both acute and chronic lung injuries, have yet to be established. Therefore, we sought to determine the potential therapeutic effects of dopamine in a murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Compared with sham-treated controls, pretreatment with dopamine (50 mg/kg body wt) ameliorated LPS-mediated edema formation and lowered myeloperoxidase activity, a measure of neutrophil infiltration. Moreover, dopamine significantly increased survival rates of LPS-treated mice, from 0–75%. Mechanistically, we found that dopamine acts through the VEGF-VEGFR2 axis to reduce pulmonary edema, as dopamine pretreatment in LPS-treated mice resulted in decreased serum VEGF, VEGFR2 phosphorylation, and endothelial nitric oxide synthase phosphorylation. We used D2DR knockout mice to confirm that dopamine acts through D2DR to block vascular permeability in our lung injury model. As expected, a D2DR agonist failed to reduce pulmonary edema in D2DR−/− mice. Taken together, our results suggest that dopamine acts through D2DR to inhibit pulmonary edema-associated vascular permeability, which is mediated through VEGF-VEGFR2 signaling and conveys protective effects in an ALI model.

scholarly journals A fraction of Prunella vulgaris spike extract inhibited neutrophil elastase and protected mice against lipopolysaccharide-induced acute lung injury

2020 ◽  
Author(s):  
Huang-Ping Yu ◽  
Chieh-Lun Cheng ◽  
Kowit-Yu Chong ◽  
Yu-Ling Huang ◽  
Kung-Ju Chen ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Neutrophil Elastase ◽  
Pulmonary Inflammation ◽  
Water Extract ◽  
Neutrophil Extracellular Trap ◽  
Human Neutrophil Elastase ◽  
Protective Effects ◽  
Prunella Vulgaris ◽  
Tissue Destruction

Abstract Background Human neutrophil elastase (HNE) is an abundantly expressed neutrophil serine protease that promotes neutrophil invasion and neutrophil extracellular trap (NET) formation, thereby mediating lung tissue destruction and enhancing pulmonary inflammation in acute lung injury (ALI). Chemical agents that target HNE and manipulate HNE level homeostasis are desired to prevent or treat ALI. Methods In a search for HNE inhibitors, traditional Chinese medicines were evaluated, leading to the identification of the water extract of spikes of Prunella vulgaris as an inhibitor of HNE activity. Using bioactivity-guided fractionation, a bioactive fraction (PVAP) that inhibited NHE activity was prepared, and its effects on lipopolysaccharide (LPS)-induced ALI were studied. Results The results suggested that PVAP elicited protective effects against LPS-induced ALI by inhibiting HNE activity, thereby reducing neutrophil invasion, pro-inflammatory cytokine release, and NET formation. Conclusions These findings illustrated the utility of PVAP as an agent for preventing ALI.

Juglone Attenuates Sepsis-Induced Acute Lung Injury via Suppression of the TLR4/Nf-κb Pathway

2020 ◽  
Vol 18 (2) ◽  
pp. 201-206
Author(s):  
Qiu Nan ◽  
Xu Xinmei ◽  
He Yingying ◽  
Fan Chengfen
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Nuclear Factor Kappa B ◽  
Cecal Ligation ◽  
Myeloperoxidase Activity ◽  
Nuclear Factor ◽  
Cecal Ligation And Puncture ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Nuclear Factor Kappa

Sepsis, with high mortality, induces deleterious organ dysfunction and acute lung injury. Natural compounds show protective effect against sepsis-induced acute lung injury. Juglone, a natural naphthoquinone, demonstrates pharmacological actions as a pro-apoptotic substrate in tumor treatment and anti-inflammation substrate in organ injury. In this study, the influence of juglone on sepsis-induced acute lung injury was investigated. First, a septic mice model was established via cecal ligation and puncture, and then verified via histopathological analysis of lung tissues, the wet/dry mass ratio and myeloperoxidase activity was determined. Cecal ligation and puncture could induce acute lung injury in septic mice, as demonstrated by alveolar damage and increase of wet/dry mass ratio and myeloperoxidase activity. However, intragastric administration juglone attenuated cecal ligation and puncture-induced acute lung injury. Secondly, cecal ligation and puncture-induced increase of inflammatory cells in bronchoalveolar lavage fluid was also alleviated by the administration of juglone. Similarly, the protective effect of juglone against cecal ligation and puncture-induced acute lung injury was accompanied by a reduction of pro-inflammatory factor secretion in bronchoalveolar lavage fluid and lung tissues. Cecal ligation and puncture could activate toll-like receptor 4/nuclear factor-kappa B signaling pathway, and administration of juglone suppressed toll-like receptor 4/nuclear factor-kappa B activation. In conclusion, juglone attenuated cecal ligation and puncture-induced lung damage and inflammatory response through inactivation of toll-like receptor 4/nuclear factor-kappa B, suggesting a potential therapeutic strategy in the treatment of sepsis-induced 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

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

2017 ◽  
Vol 312 (5) ◽  
pp. L625-L637 ◽  
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.

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