Endothelin ETB receptor-mediated mechanisms involved in oleic acid-induced acute lung injury in mice

2002 ◽  
Vol 103 (s2002) ◽  
pp. 340S-344S ◽  
Author(s):  
Cláudio L. GUIMARÃES ◽  
Patricia G. TRENTIN ◽  
Giles A. RAE
Keyword(s):  
Oleic Acid ◽  
Lung Injury ◽  
Mononuclear Cells ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Plasma Extravasation ◽  
Receptor Antagonists ◽  
Cell Counts ◽  
Etb Receptor ◽  
Eta Receptor Antagonist

The receptors underlying the endothelin-dependent component of lung plasma extravasation and leucocyte infiltration induced by oleic acid were assessed in mice. Oleic acid (1mg·kg-1 intravenously), but not endothelin-1 (up to 1nmol·kg-1 intravenously), increased accumulation of Evans blue in the lungs (excluding the trachea and main bronchi) from 11.8±3.9 to 98.6±10.7µg 1h after injection. Bosentan, the antagonist of endothelin receptors (ETA and ETB) or the selective ETB receptor antagonists Ro 46-8443 or A-192621 (administered 1h before oleic acid at doses of 30, 10 and 30mg·kg-1 respectively) reduced the effect of oleic acid by 71%, 58% and 79% respectively. However, the selective ETA receptor antagonist A-127722.5 (10mg·kg-1) was inactive. Oleic acid (2mg·kg-1, intravenously) raised the number of total leucocytes, mononuclear cells and neutrophils in broncho-alveolar lavage fluid 4h after injection. Bosentan and Ro 46-8443 (at doses of 30 and 10mg·kg-1 respectively) inhibited the neutrophil infiltration induced by oleic acid by approx. 80%. None of the antagonists modified control (basal) pulmonary microvascular permeability or total and differential cell counts. Thus, endogenous endothelins, acting via ETB receptor-dependent mechanisms, play a major role in oleic acid-induced lung injury in the mouse by promoting infiltration of circulating neutrophils and enhancement of pulmonary microvascular plasma extravasation. These findings suggest that either ETB or mixed ETA/ETB receptor antagonists might be beneficial in the treatment of the adult respiratory distress syndrome.

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 Mechanical Ventilation Enhances Acinetobacter Baumannii-induced Lung Injury Through JNK Pathways

2021 ◽  
Author(s):  
Tzyy-Bin Tsay ◽  
Wan-Hsuan Chang ◽  
Ching-Mei Hsu ◽  
Lee-Wei Chen
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Acinetobacter Baumannii ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Protein Levels ◽  
Killing Activity ◽  
Nitrite Production ◽  
Bacteria Killing ◽  
Factor Α

Abstract Background: Patients in intensive care units (ICUs) often received broad-spectrum antibiotic treatment and Acinetobacter baumannii (A.b.) and Pseudomonas aeruginosa (P.a.) were the most common pathogens causing ventilator-associated pneumonia (VAP). This study aimed to examine the effects and mechanism of mechanical ventilation (MV) on A.b.-induced lung injury and the involvement of alveolar macrophages (AMs).Methods: C57BL/6 wild-type (WT) and c-Jun N-terminal kinase knockout (JNK1−/−) mice received MV for 3 h at 2 days after nasal instillation of A.b., P.a. (1 × 106 colony-forming unit, CFU), or normal saline.Results: Intranasal instillation of 106 CFU A.b. in C57BL/6 mice induced a significant increase in total cells and protein levels in the bronchoalveolar lavage fluid (BALF) and neutrophil infiltration in the lungs. MV after A.b. instillation increases neutrophil infiltration, interleukin (IL)-6 and vascular cell adhesion molecule (VCAM) mRNA expression in the lungs and total cells, IL-6 levels, and nitrite levels in the BALF. The killing activity of AMs against A.b. was lower than against P.a. The diminished killing activity was parallel with decreased tumor necrosis factor-α production by AMs compared with with A.b. Moreover, MV decreased the A.b. and P.a. killing activity of AMs. MV after A.b. instillation induced less total cells in the BALF and nitrite production in the serum of JNK1-/- mice than those of WT mice.Conclusion: A.b. is potent in inducing neutrophil infiltration in the lungs and total protein in the BALF. MV enhances A.b.-induced lung injury through an increase in the expression of VCAM and IL-6 levels in the BALF and a decrease in the bacteria-killing activity of AMs. A lower inflammation level in JNK1-/- mice indicates that A.b.-induced VAP causes lung injury through JNK signaling pathway in the lungs.

scholarly journals Fibrocytes Ameliorate Acute Lung Injury by Decreasing Inflammatory Cytokine and Chemokine Levels and Reducing Neutrophil Accumulation in the Lung

2017 ◽  
Vol 44 (4) ◽  
pp. 1526-1536 ◽  
Author(s):  
Wenlin Tai ◽  
Yiheng Xu ◽  
Jiawei Ding ◽  
Hanxin Wu ◽  
Ming Du ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mononuclear Cells ◽  
Human Life ◽  
Severe Disease ◽  
Lavage Fluid ◽  
Neutrophil Accumulation ◽  
Peripheral Blood Mononuclear ◽  
Tnf Α ◽  
Ifn Γ

Background/Aims: Acute lung injury (ALI) remains a severe disease that threatens human life around the world. To decrease the mortality of ALI and improve ALI treatment efficacy, the development of more ALI treatments is urgently needed. Whether fibrocytes directly participate in ALI has not been studied. Therefore, a mouse model of ALI was induced with lipopolysaccharide (LPS). Methods: Fibrocytes were harvested from peripheral blood mononuclear cells of bleomycin mice and identified by using flow cytometry to detect the expression of molecular makers. The fibrocytes were injected for the treatment of acute lung injury mice. The curative effects were evaluated by using ELISA to determine the cytokines (including TNF-α, IL-6 and IFN-γ) concentrations in bronchoalveolar lavage fluid (BALF) supernatant. Results: The concentrations of cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IFN-γ) were increased in mice with ALI induced with LPS. The concentrations of TNF-α, IL-6, and IFN-γ as well as their mRNA and protein expression levels were decreased by administration of fibrocytes. The effect of fibrocytes in ameliorating ALI was time dependent. LPS treatment induced an increase in myeloperoxidase (MPO) activity, whereas the fibrocyte treatment caused inhibition of MPO activity as well as expression of the neutrophil-chemoattractant chemokine macrophage inflammatory protein 2 (MIP-2). Conclusion: Taken together, these data suggest that fibrocytes ameliorated ALI by suppressing inflammatory cytokines and chemokines as well as by decreasing the accumulation of neutrophils in the lung.

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 NADPH Oxidase 4 Signaling in a Ventilator-induced Lung Injury Mouse Model

2021 ◽  
Author(s):  
Sang Hoon Lee ◽  
Mi Hwa Shin ◽  
Ah Young Leem ◽  
Su Hwan Lee ◽  
Kyung Soo Chung ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lavage Fluid ◽  
Lung Damage ◽  
Control Group ◽  
Group 4 ◽  
Ventilator Induced Lung Injury ◽  
Cell Counts ◽  
Group 5 ◽  
Group 2

Abstract For patients with acute respiratory distress syndrome, a ventilator is essential to supply oxygen to tissues, but it may also cause lung damage. We investigated the role of NOX4 in a ventilator-induced lung injury (VILI) model.Wild-type (WT) male C57BL/6J mice and NOX4 knockout (KO) male mice were divided into five groups: (1) control group; (2) high tidal ventilation (HTV) group: WT mice + HTV; (3) NOX4 KO group; (4) NOX4 KO with HTV group; (5) NOX4 inhibitor group: WT mice + HTV + NOX4 inhibitor. In addition, the relationship between EphA2 (which is related to lung injury) and NOX4 was investigated using EphA2 KO mice, and NOX4 levels in the bronchoalveolar lavage fluid (BALF) of 38 patients with pneumonia were examined.In the NOX4 inhibitor group, cell counts and protein concentrations from BALF were significantly lower than those in the HTV group (both, p<0.001). In the NOX4 KO group and the NOX4 inhibitor group, EphA2 levels were significantly lower than those in the HTV group (p<0.001). NOX4 levels were significantly higher in patients with pneumonia and patients who received ventilator treatment in the ICU.In the VILI model, it may be possible to block VILI using NOX4 antibodies.

scholarly journals Respiratory syncytial virus infection increases chlorine-induced airway hyperresponsiveness

2015 ◽  
Vol 309 (3) ◽  
pp. L205-L210 ◽  
Author(s):  
Weifeng Song ◽  
Zhihong Yu ◽  
Stephen F. Doran ◽  
Namasivayam Ambalavanan ◽  
Chad Steele ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Lung Injury ◽  
Airway Hyperresponsiveness ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Infection Model ◽  
Type 2 Cytokines ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
First Time

Exposure to chlorine (Cl2) damages airway and alveolar epithelia resulting in acute lung injury and reactive airway hyperresponsiveness (AHR) to methacholine. However, little is known about the effect of preexisting respiratory disease on Cl2-induced lung injury. By using a murine respiratory syncytial virus (RSV) infection model, we found that preexisting RSV infection increases Cl2 (187 ppm for 30 min)-induced lung inflammation and airway AHR at 24 h after exposure (5 days after infection). RSV infection and Cl2 exposure synergistically induced oxygen desaturation and neutrophil infiltration and increased MCP-1, MIP-1β, IL-10, IFN-γ, and RANTES concentrations in the bronchoalveolar lavage fluid (BALF). In contrast, levels of type 2 cytokines (i.e., IL-4, IL-5, IL-9, and IL-13) were not significantly affected by either RSV infection or Cl2 exposure. Cl2 exposure, but not RSV infection, induced AHR to methacholine challenge as measured by flexiVent. Moreover, preexisting RSV infection amplified BALF levels of hyaluronan (HA) and AHR. The Cl2-induced AHR was mitigated by treatment with inter-α-trypsin inhibitor antibody, which inhibits HA signaling, suggesting a mechanism of HA-mediated AHR from exacerbated oxidative injury. Our results show for the first time that preexisting RSV infection predisposes the lung to Cl2-induced injury. These data emphasize the necessity for further research on the effects of Cl2 in vulnerable populations and the development of appropriate treatments.

scholarly journals Mechanical ventilation enhances Acinetobacter baumannii-induced lung injury through JNK pathways

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Tzyy-Bin Tsay ◽  
Wan-Hsuan Chang ◽  
Ching-Mei Hsu ◽  
Lee-Wei Chen
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Acinetobacter Baumannii ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Cell Number ◽  
Nitric Oxide Synthase Inhibitor ◽  
Killing Activity ◽  
Nitrite Production ◽  
Synthase Inhibitor

Abstract Background Patients in intensive care units (ICUs) often received broad-spectrum antibiotic treatment and Acinetobacter baumannii (A.b.) and Pseudomonas aeruginosa (P.a.) were the most common pathogens causing ventilator-associated pneumonia (VAP). This study aimed to examine the effects and mechanism of mechanical ventilation (MV) on A.b.-induced lung injury and the involvement of alveolar macrophages (AMs). Methods C57BL/6 wild-type (WT) and c-Jun N-terminal kinase knockout (JNK1−/−) mice received MV for 3 h at 2 days after nasal instillation of A.b., P.a. (1 × 106 colony-forming unit, CFU), or normal saline. Results Intranasal instillation of 106 CFU A.b. in C57BL/6 mice induced a significant increase in total cells and protein levels in the bronchoalveolar lavage fluid (BALF) and neutrophil infiltration in the lungs. MV after A.b. instillation increases neutrophil infiltration, interleukin (IL)-6 and vascular cell adhesion molecule (VCAM) mRNA expression in the lungs and total cells, IL-6 levels, and nitrite levels in the BALF. The killing activity of AMs against A.b. was lower than against P.a. The diminished killing activity was parallel with decreased tumor necrosis factor-α production by AMs compared with A.b. Inducible nitric oxide synthase inhibitor, S-methylisothiourea, decreased the total cell number in BALF on mice receiving A.b. instillation and ventilation. Moreover, MV decreased the A.b. and P.a. killing activity of AMs. MV after A.b. instillation induced less total cells in the BALF and nitrite production in the serum of JNK1−/− mice than those of WT mice. Conclusion A.b. is potent in inducing neutrophil infiltration in the lungs and total protein in the BALF. MV enhances A.b.-induced lung injury through an increase in the expression of VCAM and IL-6 levels in the BALF and a decrease in the bacteria-killing activity of AMs. A lower inflammation level in JNK1−/− mice indicates that A.b.-induced VAP causes lung injury through JNK signaling pathway in the lungs.

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 NADPH Oxidase 4 Signaling in a Ventilator-Induced Lung Injury Mouse Model

2020 ◽  
Author(s):  
Sang Hoon Lee ◽  
Mi Hwa Shin ◽  
Ah Young Leem ◽  
Su Hwan Lee ◽  
Kyung Soo Chung ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lavage Fluid ◽  
Lung Damage ◽  
Control Group ◽  
Nadph Oxidase 4 ◽  
Ventilator Induced Lung Injury ◽  
Oxygen Fraction ◽  
Cell Counts ◽  
The Relationship

Abstract BackgroundFor patients with acute respiratory distress syndrome (ARDS), a ventilator is essential to supply oxygen to tissues, but it may also cause lung damage. In this study, we investigated the role of NOX4 in lung injury using NOX4 knockout (KO) mice and NOX4 inhibitors in a ventilator-induced lung injury (VILI) model.MethodsWild-type male C57BL/6J mice and NOX4 KO male mice were divided into five groups: (1) control group: wild-type (WT) mice + non-ventilator; (2) high tidal ventilation (HTV) group: WT mice + HTV; (3) NOX4 KO group: NOX4 KO + non-ventilator; (4) NOX4 KO with HTV group: NOX4 KO mice + HTV; (5) NOX4 inhibitor group: WT mice + HTV + post-treatment (anti-GKT 137831 inhibitor). In the VILI model, the supine position was maintained at 24 mL/kg volume, 0 cm H2O PEEP, 100/min respiratory rate, and 0.21 inspired oxygen fraction. In the NOX4 inhibitor group, 50 μL anti-GKT 137831 inhibitor was injected intraperitoneally, 2 h after ventilator use. After 5 h of HTV, mice in the ventilator group were euthanized, and their lung tissues were obtained for further analysis. In addition, the relationship between EphA2 (which is related to lung injury) and NOX4 was investigated using EphA2 KO mice, and NOX4 levels in the bronchoalveolar lavage fluid (BALF) of 38 patients with pneumonia were examined.ResultsCell counts from BALFs were significantly lower (p<0.01) in the NOX4 KO with HTV group compared to that in the HTV group. In the NOX4 inhibitor group, cell counts and protein concentrations were significantly lower than those in the HTV group (both, p<0.001). In the NOX4 KO mouse group and the NOX4 inhibitor group, EphA2 levels were significantly lower than those in the HTV group (both, p<0.001). In patients with respiratory disease, NOX4 levels were significantly higher in patients with pneumonia and patients who received ventilator treatment in the intensive care unit.ConclusionsIn the VILI model, NOX4 expression is significantly associated with Eph-ephrin signaling. It may be possible to block VILI using NOX4 antibodies.

scholarly journals Attenuation of pulmonary injury by an inhaled MMP inhibitor in the endotoxin lung injury model

2020 ◽  
Vol 319 (6) ◽  
pp. L1036-L1047
Author(s):  
Adam Gerber ◽  
Monica Goldklang ◽  
Kyle Stearns ◽  
Xinran Ma ◽  
Rui Xiao ◽  
...  
Keyword(s):  
Lung Injury ◽  
Pulmonary Edema ◽  
Pulmonary Inflammation ◽  
Neutrophil Migration ◽  
Neutrophil Infiltration ◽  
Vascular Integrity ◽  
Pulmonary Vascular Permeability ◽  
Mmp Inhibitor ◽  
Cell Counts ◽  
Lung Injury Model

Acute respiratory distress syndrome (ARDS) is characterized by pulmonary edema and poor gas exchange resulting from severe inflammatory lung injury. Neutrophilic infiltration and increased pulmonary vascular permeability are hallmarks of early ARDS and precipitate a self-perpetuating cascade of inflammatory signaling. The biochemical processes initiating these events remain unclear. Typically associated with extracellular matrix degradation, recent data suggest matrix metalloproteinases (MMPs) are regulators of pulmonary inflammation. To demonstrate that inhalation of a broad MMP inhibitor attenuates LPS induced pulmonary inflammation. Nebulized CGS27023AM (CGS) was administered to LPS-injured mice. Pulmonary CGS levels were examined by mass spectroscopy. Inflammatory scoring of hematoxylin-eosin sections, examination of vascular integrity via lung wet/dry and bronchoalveolar lvage/serum FITC-albumin ratios were performed. Cleaved caspase-3 levels were also assessed. Differential cell counts and pulse-chase labeling were utilized to determine the effects of CGS on neutrophil migration. The effects of CGS on human neutrophil migration and viability were examined using Boyden chambers and MTT assays. Nebulization successfully delivered CGS to the lungs. Treatment decreased pulmonary inflammatory scores, edema, and apoptosis in LPS treated animals. Neutrophil chemotaxis was reduced by CGS treatment, with inhalation causing significant reductions in both the total number and newly produced bromodeoxyuridine-positive cells infiltrating the lung. Mechanistic studies on cells isolated from humans demonstrate that CGS-treated neutrophils exhibit decreased chemotaxis. The protective effect observed following treatment with a nonspecific MMP inhibitor indicates that one or more MMPs mediate the development of pulmonary edema and neutrophil infiltration in response to LPS injury. In accordance with this, inhaled MMP inhibitors warrant further study as a potential new therapeutic avenue for treatment of acute lung injury.

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