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 Milonine Protects Against Acute Lung Injury By Modulating The Akt And NF-κB Signaling Pathway

2021 ◽  
Author(s):  
Larissa Rodrigues Bernardo ◽  
Laércia Karla Diega Paiva Ferreira ◽  
Larissa Adilis Maria Paiva Ferreira ◽  
Cosmo Isaías Duvirgens Vieira ◽  
João Batista de Oliveira ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Hydrophobic Interactions ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Lung Edema ◽  
Toll Like Receptor 4 ◽  
Downstream Signaling ◽  
Tnf Α ◽  
Anti Inflammatory

Abstract Acute lung injury (ALI) is an inflammation that triggers acute respiratory distress syndrome (ARDS) with perialveolar neutrophil infiltration, alveolar-capillary barrier damage, and lung edema. Activation of the toll-like receptor 4 complex and its downstream signaling pathways are responsible for the cytokine storm and cause alveolar damage on ARDS. Due to the complexity of inflammatory events on ALI, a defined pharmacotherapy has not been established. Thus, this study aimed to evaluate the anti-inflammatory potential of milonine, an alkaloid of Cissampelos sympodialis Eichl, in an ALI experimental model. BALB/c mice were lipopolysaccharide (LPS)-challenged and treated with milonine at 2.0 mg/kg. Twenty-four hours later, the bronchoalveolar lavage fluid (BALF), peripheral blood, and lungs were collected for cellular and molecular analysis. The milonine treatment decreased the inflammatory cell migration (principally neutrophils) to the alveolar cavity, the protein exudate, the pulmonary edema, and the level of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) into the BALF. The systemic level of IL-6 level was also reduced. In the lung tissue, milonine reduced the bronchoalveolar damage. The milonine docking analyzes demonstrated that the molecule formed hydrophobic interactions with the amino-acids Ile124 and Phe126 of the TLR4/MD2 groove. Indeed, the anti-inflammatory effect of milonine was due to the negative regulation of cytoplasmic kinase-Akt and NF-κB by interacting with the TLR4/MD2 complex. Therefore, milonine is an effective inflammatory modulator by blocking the interaction of the LPS-TLR4/MD2 complex and downregulating the intracellular inflammatory pathway axis being a potential molecule for the treatment of ALI.

scholarly journals Nedd8 modification of Cullin-5 regulates lipopolysaccharide-induced acute lung injury

2017 ◽  
Vol 313 (1) ◽  
pp. L104-L114 ◽  
Author(s):  
Ziyan Zhu ◽  
Lei Sun ◽  
Rui Hao ◽  
Hongchao Jiang ◽  
Feng Qian ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Tumor Necrosis Factor Receptor ◽  
Intratracheal Instillation ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Wild Type ◽  
Cullin 5 ◽  
Lung Liquid ◽  
Deficient Mice

Lung infections are major causes of acute lung injury (ALI), with limited effective treatment available. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an essential adaptor regulating Toll-like receptors (TLRs). We recently identified Cullin-5 (Cul-5) as a prominent component in the regulation of TRAF6 polyubiquitination, but its physiological significance in ALI has not been explored. In this study, we investigated the potential role of Cul-5 in regulating ALI using mice receiving intratracheal instillation of LPS. We observed that Cul-5-deficient mice displayed reduced lung injury compared with wild-type mice as evidenced by histological analysis, alveolar neutrophil infiltration, and lung liquid accumulation. In addition, inflammatory cytokine expression in bronchoalveolar lavage fluid and lung tissue was also markedly reduced in LPS-treated Cul-5-deficient mice. Interestingly, intratracheal adoptive transfer of Cul-5+/− but not Cul-5+/+ macrophages attenuated neutrophil recruitment, alveolar inflammation, and loss of barrier function in LPS-challenged wild-type mice. Finally, we demonstrated that Cul-5 neddylation following LPS exposure induced Cul-5 and TRAF6 interaction and, thereby, TFAR6 polyubiquitination, leading to NF-κB activation and generation of proinflammatory cytokines. Our data show that neural precursor cell expressed developmentally downregulated protein 8 (Nedd8) modification of Cul-5 is required for its interaction with TRAF6 and activation of the TLR4-TRAF6 signaling pathway in LPS-induced ALI, a feature that may be explored for therapeutic intervention.

scholarly journals Protein S is Protective in Acute Lung Injury by Inhibiting Cell Apoptosis

2019 ◽  
Vol 20 (5) ◽  
pp. 1082 ◽  
Author(s):  
Prince Baffour Tonto ◽  
Taro Yasuma ◽  
Tetsu Kobayashi ◽  
Corina D’Alessandro-Gabazza ◽  
Masaaki Toda ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Transgenic Mice ◽  
Lung Tissue ◽  
Cell Apoptosis ◽  
Inflammatory Cell ◽  
Protein S ◽  
Inflammatory Cell Infiltration ◽  
Human Protein ◽  
Wild Type

Acute lung injury is a fatal disease characterized by inflammatory cell infiltration, alveolar-capillary barrier disruption, protein-rich edema, and impairment of gas exchange. Protein S is a vitamin K-dependent glycoprotein that exerts anticoagulant, immunomodulatory, anti-inflammatory, anti-apoptotic, and neuroprotective effects. The aim of this study was to evaluate whether human protein S inhibits cell apoptosis in acute lung injury. Acute lung injury in human protein S transgenic and wild-type mice was induced by intratracheal instillation of lipopolysaccharide. The effect of human protein S on apoptosis of lung tissue cells was evaluated by Western blotting. Inflammatory cell infiltration, alveolar wall thickening, myeloperoxidase activity, and the expression of inflammatory cytokines were reduced in human protein S transgenic mice compared to the wild-type mice after lipopolysaccharide instillation. Apoptotic cells and caspase-3 activity were reduced while phosphorylation of extracellular signal-regulated kinase was enhanced in the lung tissue from human protein S transgenic mice compared to wild-type mice after lipopolysaccharide instillation. The results of this study suggest that human protein S is protective in lipopolysaccharide-induced acute lung injury by inhibiting apoptosis of lung cells.

Therapeutic Effects of Baicalin on Lipopolysaccharide-Induced Acute Lung Injury in Rats

2008 ◽  
Vol 36 (02) ◽  
pp. 301-311 ◽  
Author(s):  
Kun-Lun Huang ◽  
Chien-Sheng Chen ◽  
Ching-Wang Hsu ◽  
Min-Hui Li ◽  
Hung Chang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Weight Ratio ◽  
Histological Finding ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Blue Dye ◽  
Therapeutic Effects ◽  
Lung Weight ◽  
Lactate Dehydrogenase Activity

Baicalin is a flavonoid present in many traditional Chinese medicines. A number of studies show that baicalin has anti-inflammatory actions and protects against a variety of tissue and organ injuries. The effect of baicalin in lipopolysaccharide (LPS)-induced acute lung injury is not well studied. In this study, typically acute lung injury was induced in rat by intratracheal injection of LPS, which increased lactate dehydrogenase activity and protein content in bronchoalveolar lavage fluid, wet/dry lung weight ratio, Evan's blue dye leakage, and neutrophil infiltration. Baicalin (20 mg/kg) was administrated 1 hour before or 30 min after LPS injection. Both pre and post-treatment with baicalin attenuated the increase of these parameters and improved histological finding. Our results suggest that baicalin has a therapeutic effect on LPS-induced acute lung injury.

scholarly journals Anti-Inflammatory Effects of Ellagic Acid on Acute Lung Injury Induced by Acid in Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Daniely Cornélio Favarin ◽  
Maxelle Martins Teixeira ◽  
Ednéia Lemos de Andrade ◽  
Claudiney de Freitas Alves ◽  
Javier Emilio Lazo Chica ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Ellagic Acid ◽  
Neutrophil Migration ◽  
Lavage Fluid ◽  
Positive Control ◽  
Oral Route ◽  
Dexamethasone Treatment ◽  
Acid Aspiration ◽  
Anti Inflammatory

Acute lung injury (ALI) is characterized by alveolar edema and uncontrolled neutrophil migration to the lung, and no specific therapy is still available. Ellagic acid, a compound present in several fruits and medicinal plants, has shown anti-inflammatory activity in several experimental disease models. We used the nonlethal acid aspiration model of ALI in mice to determine whether preventive or therapeutic administration of ellagic acid (10 mg/kg; oral route) could interfere with the development or establishment of ALI inflammation. Dexamethasone (1 mg/kg; subcutaneous route) was used as a positive control. In both preventive and therapeutic treatments, ellagic acid reduced the vascular permeability changes and neutrophil recruitment to the bronchoalveolar lavage fluid (BALF) and to lung compared to the vehicle. In addition, the ellagic acid accelerated the resolution for lung neutrophilia. Moreover, ellagic acid reduced the COX-2-induced exacerbation of inflammation. These results were similar to the dexamethasone. However, while the anti-inflammatory effects of dexamethasone treatment were due to the reduced activation of NF-κB and AP-1, the ellagic acid treatment led to reduced BALF levels of IL-6 and increased levels of IL-10. In addition, dexamethasone treatment reduced IL-1β. Together, these findings identify ellagic acid as a potential therapeutic agent for ALI-associated inflammation.

scholarly journals Prophylactic Inhalation of L-Alanyl-L-Glutamine Enhances Heat Shock Protein 72 and Attenuates Endotoxin-Induced Lung Injury in Rats

2015 ◽  
pp. 505-512 ◽  
Author(s):  
I.-C. CHUANG ◽  
M.-S. HUANG ◽  
L.-J. HUANG ◽  
S.-H. CHOU ◽  
T.-N. TSAI ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Heat Shock ◽  
Lung Injury ◽  
Heat Shock Protein ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Lung Damage ◽  
Lung Injury Score ◽  
Hsp70 Expression ◽  
Saline Administration

Studies have demonstrated that heat shock protein 70 (HSP70) plays an important role in the protection of stressed organisms. The development of strategies for enhancing HSPs expression may provide novel means of minimizing inflammatory lung conditions, such as acute lung injury. This study aimed to examine the effect of L-alanyl-L-glutamine (GLN) inhalation in enhancing pulmonary HSP72 (inducible HSP70) expression and attenuating lung damage in a model of acute lung injury induced by Lipopolysaccharide (LPS) inhalation. The experimental rats were randomly assigned to one of four experimental groups: (1) NS: saline inhalation; (2) NS-LPS: pretreatment by saline inhalation 12 h before LPS inhalation; (3) GLN: glutamine inhalation; (4) GLN-LPS: pretreatment by glutamine inhalation 12 h before LPS inhalation. The results show that GLN compared with saline administration, led to significant increase in lung HSP72 both in non LPS-treated rats and LPS-treated rats. In LPS-treated rats, pretreatment by GLN inhalation produced less lung injury as evidenced by the decrease in lung injury score and dramatic decrease in lactate dehydrogenase (LDH) activity and polymorphonuclear leukocyte cell differentiation counts (PMN %) in the bronchoalveolar lavage fluid. The study indicates that prophylactic glutamine inhalation associated with the enhancement of HSP72 synthesis attenuates tissue damage in experimental lung injury.

scholarly journals Anti-Inflammatory and Reactive Oxygen Species Suppression through Aspirin Pretreatment to Treat Hyperoxia-Induced Acute Lung Injury in NF-κB–Luciferase Inducible Transgenic Mice

Antioxidants ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 429 ◽  
Author(s):  
Chuan-Mu Chen ◽  
Yu-Tang Tung ◽  
Chi-Hsuan Wei ◽  
Po-Ying Lee ◽  
Wei Chen
Keyword(s):  
Reactive Oxygen Species ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Transgenic Mice ◽  
In Vivo Imaging ◽  
Reactive Oxygen ◽  
Luciferase Expression ◽  
Oxygen Species ◽  
Anti Inflammatory

Acute lung injury (ALI), a common cause of morbidity and mortality in intensive care units, results from either direct intra-alveolar injury or indirect injury following systemic inflammation and oxidative stress. Adequate tissue oxygenation often requires additional supplemental oxygen. However, hyperoxia causes lung injury and pathological changes. Notably, preclinical data suggest that aspirin modulates numerous platelet-mediated processes involved in ALI development and resolution. Our previous study suggested that prehospital aspirin use reduced the risk of ALI in critically ill patients. This research uses an in vivo imaging system (IVIS) to investigate the mechanisms of aspirin’s anti-inflammatory and antioxidant effects on hyperoxia-induced ALI in nuclear factor κB (NF-κB)–luciferase transgenic mice. To define mechanisms through which NF-κB causes disease, we developed transgenic mice that express luciferase under the control of NF-κB, enabling real-time in vivo imaging of NF-κB activity in intact animals. An NF-κB-dependent bioluminescent signal was used in transgenic mice carrying the luciferase genes to monitor the anti-inflammatory effects of aspirin. These results demonstrated that pretreatment with aspirin reduced luciferase expression, indicating that aspirin reduces NF-κB activation. In addition, aspirin reduced reactive oxygen species expression, the number of macrophages, neutrophil infiltration and lung edema compared with treatment with only hyperoxia treatment. In addition, we demonstrated that pretreatment with aspirin significantly reduced the protein levels of phosphorylated protein kinase B, NF-κB and tumor necrosis factor α in NF-κB–luciferase+/+ transgenic mice. Thus, the effects of aspirin on the anti-inflammatory response and reactive oxygen species suppressive are hypothesized to occur through the NF-κB signaling pathway. This study demonstrated that aspirin exerts a protective effect for hyperoxia-induced lung injury and thus is currently the drug conventionally used for hyperoxia-induced lung injury.

scholarly journals Anti-Inflammatory and Anticoagulative Effects of Paeonol on LPS-Induced Acute Lung Injury in Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Pin-Kuei Fu ◽  
Chieh-Liang Wu ◽  
Tung-Hu Tsai ◽  
Ching-Liang Hsieh
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Interleukin 1 ◽  
Intraperitoneal Administration ◽  
Lavage Fluid ◽  
Polymorphonuclear Neutrophils ◽  
Sprague Dawley ◽  
Intratracheal Administration ◽  
Sprague Dawley Rats ◽  
Anti Inflammatory

Paeonol is an active component of Moutan Cortex Radicis and is widely used as an analgesic, antipyretic, and anti-inflammatory agent in traditional Chinese medicine. We wanted to determine the role of paeonol in treating adult respiratory distress syndrome (ARDS). We established an acute lung injury (ALI) model in Sprague-Dawley rats, which was similar to ARDS in humans, using intratracheal administration of lipopolysaccharide (LPS). The intraperitoneal administration of paeonol successfully reduced histopathological scores and attenuated myeloperoxidase-reactive cells as an index of polymorphonuclear neutrophils infiltration and also reduces inducible nitric oxide synthase expression in the lung tissue, at 16 h after LPS administration. In addition, paeonol reduced proinflammatory cytokines in bronchoalveolar lavage fluid, including tumor-necrosis factor-α, interleukin-1β, interleukin-6, and plasminogen-activated inhibition factor-1. These results indicated that paeonol successfully attenuates inflammatory and coagulation reactions to protect against ALI.

Haptoglobin reduces lung injury associated with exposure to blood

2003 ◽  
Vol 284 (2) ◽  
pp. L402-L409 ◽  
Author(s):  
Funmei Yang ◽  
David J. Haile ◽  
Franklin G. Berger ◽  
Damon C. Herbert ◽  
Emily Van Beveren ◽  
...  
Keyword(s):  
Lung Injury ◽  
Transgenic Mice ◽  
Alveolar Macrophages ◽  
Ferritin Level ◽  
Protective Role ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Intracellular Iron ◽  
High Level ◽  
Mouse Lungs

The biological functions of the acute- phase protein haptoglobin (Hp) may be related to its ability to bind hemoglobin (Hb) or to modulate immune response. Hp is expressed at a high level in lung cells, yet its protective role(s) in the lung is not known. With the use of transgenic mice overexpressing Hp in alveolar macrophages, we demonstrated that Hp diminished Hb-induced lung injury when the lung was exposed to whole blood. In transgenic mouse lungs, Hb was more efficiently removed, and the induction of stress- responsive heme oxygenase-1 gene was significantly lower when compared with wild-type mice. At 24 h after blood treatment, the ferritin level that serves as an index for intracellular iron content was also lower in alveolar macrophages in transgenic mice than in wild-type mice. We propose that an Hp-mediated Hb catabolism process exists in alveolar macrophages. This process is likely coupled to an iron mobilization pathway and may be an efficient mechanism to reduce oxidative damage associated with hemolysis.

scholarly journals Plasma glutamate–modulated interaction of A2AR and mGluR5 on BMDCs aggravates traumatic brain injury–induced acute lung injury

2013 ◽  
Vol 210 (4) ◽  
pp. 839-851 ◽  
Author(s):  
Shuang-Shuang Dai ◽  
Hao Wang ◽  
Nan Yang ◽  
Jian-Hong An ◽  
Wei Li ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Acute Lung Injury ◽  
Brain Injury ◽  
Lung Injury ◽  
Metabotropic Glutamate Receptor ◽  
White Blood Cells ◽  
Protective Role ◽  
Lung Damage ◽  
Severe Tbi ◽  
Proinflammatory Effect

The bone marrow–derived cell (BMDC)–associated inflammatory response plays a key role in the development of acute lung injury (ALI). Activation of adenosine A2A receptor (A2AR) is generally considered to be antiinflammatory, inhibiting BMDC activities to protect against ALI. However, in the present study, we found that in a mouse model of neurogenic ALI induced by severe traumatic brain injury (TBI), BMDC A2AR exerted a proinflammatory effect, aggravating lung damage. This is in contrast to the antiinflammatory effect observed in the mouse oleic acid–induced ALI model (a nonneurogenic ALI model.) Moreover, the A2AR agonist CGS21680 aggravated, whereas the antagonist ZM241385 attenuated, the severe TBI-induced lung inflammatory damage in mice. Further investigation of white blood cells isolated from patients or mouse TBI models and of cultured human or mouse neutrophils demonstrated that elevated plasma glutamate after severe TBI induced interaction between A2AR and the metabotropic glutamate receptor 5 (mGluR5) to increase phospholipase C–protein kinase C signaling, which mediated the proinflammatory effect of A2AR. These results are in striking contrast to the well-known antiinflammatory and protective role of A2AR in nonneurogenic ALI and indicate different therapeutic strategies should be used for nonneurogenic and neurogenic ALI treatment when targeting A2AR.

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