scholarly journals Obesity Attenuates Ventilator-Induced Lung Injury by Modulating the STAT3–SOCS3 Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Shih-Wei Wu ◽  
Chung-Kan Peng ◽  
Shu-Yu Wu ◽  
Yu Wang ◽  
Sung-Sen Yang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lung Injury Score ◽  
Protective Mechanism ◽  
Free Access ◽  
Obese Mice ◽  
Wild Type ◽  
Barrier Dysfunction ◽  
Ventilator Induced Lung Injury ◽  
Nfκb Pathway ◽  
Set Up

BackgroundVentilator-induced lung injury (VILI) is characterized by vascular barrier dysfunction and suppression of alveolar fluid clearance (AFC). Obesity itself leads to chronic inflammation, which may initiate an injurious cascade to the lungs and simultaneously induce a protective feedback. In this study, we investigated the protective mechanism of obesity on VILI in a mouse model.MethodsThe VILI model was set up via 6-h mechanical ventilation with a high tidal volume. Parameters including lung injury score, STAT3/NFκB pathway, and AFC were assessed. Mice with diet-induced obesity were obtained by allowing free access to a high-fat diet since the age of 3 weeks. After a 9-week diet intervention, these mice were sacrificed at the age of 12 weeks. The manipulation of SOCS3 protein was achieved by siRNA knockdown and pharmaceutical stimulation using hesperetin. WNK4 knockin and knockout obese mice were used to clarify the pathway of AFC modulation.ResultsObesity itself attenuated VILI. Knockdown of SOCS3 in obese mice offset the protection against VILI afforded by obesity. Hesperetin stimulated SOCS3 upregulation in nonobese mice and provided protection against VILI. In obese mice, the WNK4 axis was upregulated at the baseline, but was significantly attenuated after VILI compared with nonobese mice. At the baseline, the manipulation of SOCS3 by siRNA and hesperetin also led to the corresponding alteration of WNK4, albeit to a lesser extent. After VILI, WNK4 expression correlated with STAT3/NFκB activation, regardless of SOCS3 status. Obese mice carrying WNK4 knockout had VILI with a severity similar to that of wild-type obese mice. The severity of VILI in WNK4-knockin obese mice was counteracted by obesity, similar to that of wild-type nonobese mice only.ConclusionsObesity protects lungs from VILI by upregulating SOCS3, thus suppressing the STAT3/NFκB inflammatory pathway and enhancing WNK4-related AFC. However, WNK4 activation is mainly from direct NFκB downstreaming, and less from SOCS3 upregulation. Moreover, JAK2–STAT3/NFκB signaling predominates the pathogenesis of VILI. Nevertheless, the interaction between SOCS3 and WNK4 in modulating VILI in obesity warrants further investigation.

scholarly journals Apoptosis signal-regulating kinase-1 promotes inflammasome priming in macrophages

2019 ◽  
Vol 316 (3) ◽  
pp. L418-L427 ◽  
Author(s):  
Camille N. Immanuel ◽  
Bin Teng ◽  
Brittany Dong ◽  
Elizabeth M. Gordon ◽  
Joseph A. Kennedy ◽  
...  
Keyword(s):  
Lung Injury ◽  
Neutrophil Infiltration ◽  
Response To Treatment ◽  
Wild Type ◽  
Macrophage Cell Line ◽  
Macrophage Cell ◽  
Proinflammatory Response ◽  
Caspase 1 ◽  
Ventilator Induced Lung Injury ◽  
First Time

We previously showed that mice deficient in apoptosis signal-regulating kinase-1 (ASK1) were partially protected against ventilator-induced lung injury. Because ASK1 can promote both cell death and inflammation, we hypothesized that ASK1 activation regulates inflammasome-mediated inflammation. Mice deficient in ASK1 expression (ASK1−/−) exhibited significantly less inflammation and lung injury (as measured by neutrophil infiltration, IL-6, and IL-1β) in response to treatment with inhaled lipopolysaccharide (LPS) compared with wild-type (WT) mice. To determine whether this proinflammatory response was mediated by ASK1, we investigated inflammasome-mediated responses to LPS in primary macrophages and bone marrow-derived macrophages (BMDMs) from WT and ASK1−/− mice, as well as the mouse alveolar macrophage cell line MH-S. Cells were treated with LPS alone for priming or LPS followed by ATP for activation. When macrophages were stimulated with LPS followed by ATP to activate the inflammasome, we found a significant increase in secreted IL-1β from WT cells compared with ASK1-deficient cells. LPS priming stimulated an increase in NOD-like receptor 3 (NLRP3) and pro-IL-1β in WT BMDMs, but expression of NLRP3 was significantly decreased in ASK1−/− BMDMs. Subsequent ATP treatment stimulated an increase in cleaved caspase-1 and IL-1β in WT BMDMs compared with ASK1−/− BMDMs. Similarly, treatment of MH-S cells with LPS + ATP caused an increase in both cleaved caspase-1 and IL-1β that was diminished by the ASK-1 inhibitor NQDI1. These results demonstrate, for the first time, that ASK1 promotes inflammasome priming.

scholarly journals Pre-Treatment with Allopurinol or Uricase Attenuates Barrier Dysfunction but Not Inflammation during Murine Ventilator-Induced Lung Injury

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e50559 ◽  
Author(s):  
Maria T. Kuipers ◽  
Hamid Aslami ◽  
Alexander P. J. Vlaar ◽  
Nicole P. Juffermans ◽  
Anita M. Tuip-de Boer ◽  
...  
Keyword(s):  
Lung Injury ◽  
Barrier Dysfunction ◽  
Ventilator Induced Lung Injury ◽  
Pre Treatment

Clara cell secretory protein and phospholipase A2 activity modulate acute ventilator-induced lung injury in mice

2005 ◽  
Vol 98 (4) ◽  
pp. 1264-1271 ◽  
Author(s):  
Sawako Yoshikawa ◽  
Takashige Miyahara ◽  
Susan D. Reynolds ◽  
Barry R. Stripp ◽  
Mircea Anghelescu ◽  
...  
Keyword(s):  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Dry Weight ◽  
High Volume ◽  
Secretory Protein ◽  
Clara Cell ◽  
Wild Type ◽  
Clara Cell Secretory Protein ◽  
Ventilator Induced Lung Injury ◽  
Volume Ventilation

Lung vascular permeability is acutely increased by high-pressure and high-volume ventilation. To determine the roles of mechanically activated cytosolic PLA2 (cPLA2) and Clara cell secretory protein (CCSP), a modulator of cPLA2 activity, we compared lung injury with and without a PLA2 inhibitor in wild-type mice and CCSP-null mice (CCSP−/−) ventilated with high and low peak inflation pressures (PIP) for 2- or 4-h periods. After ventilation with high PIP, we observed significant increases in the bronchoalveolar lavage albumin concentrations, lung wet-to-dry weight ratios, and lung myeloperoxidase in both genotypes compared with unventilated controls and low-PIP ventilated mice. All injury variables except myeloperoxidase were significantly greater in the CCSP−/− mice relative to wild-type mice. Inhibition of cPLA2 in wild-type and CCSP−/− mice ventilated at high PIP for 4 h significantly reduced bronchoalveolar lavage albumin and total protein and lung wet-to-dry weight ratios compared with vehicle-treated mice of the same genotype. Membrane phospho-cPLA2 and cPLA2 activities were significantly elevated in lung homogenates of high-PIP ventilated mice of both genotypes but were significantly higher in the CCSP−/− mice relative to the wild-type mice. Inhibition of cPLA2 significantly attenuated both the phospho-cPLA2 increase and increased cPLA2 activity due to high-PIP ventilation. We propose that mechanical activation of the cPLA2 pathway contributes to acute high PIP-induced lung injury and that CCSP may reduce this injury through inhibition of the cPLA2 pathway and reduction of proinflammatory products produced by this pathway.

scholarly journals Plasminogen Activator Inhibitor-Type I Gene Deficient Mice Show Reduced Influx of Neutrophils in Ventilator-Induced Lung Injury

2011 ◽  
Vol 2011 ◽  
pp. 1-11
Author(s):  
Esther K. Wolthuis ◽  
Alexander P. J. Vlaar ◽  
Jorrit-Jan H. Hofstra ◽  
Joris J. T. H. Roelofs ◽  
Vivian de Waard ◽  
...  
Keyword(s):  
Lung Injury ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Lavage Fluid ◽  
Type I ◽  
Wild Type ◽  
Ventilator Induced Lung Injury ◽  
Deficient Mice ◽  
Activator Inhibitor ◽  
Pai 1

Ventilator-induced lung injury (VILI) is associated with inhibition of the fibrinolytic system secondary to increased production of plasminogen activator inhibitor- (PAI-)1. To determine the role of PAI-1 on pulmonary coagulopathy and inflammation during mechanical ventilation, PAI-1 gene-deficient mice and their wild-type littermates were anesthetized (control), or anesthetized, tracheotomized and subsequently ventilated for 5 hours with either low tidal volumes () or high tidal volumes (). VILI was assessed by pulmonary coagulopathy, lung wet-to-dry ratios, total protein level in bronchoalveolar lavage fluid, neutrophil influx, histopathology, and pulmonary and plasma cytokine levels. Ventilation resulted in pulmonary coagulopathy and inflammation, with more injury following ventilation with as compared to . In PAI-1 gene-deficient mice, the influx of neutrophils in the pulmonary compartment was attenuated, while increased levels of pulmonary cytokines were found. Other endpoints of VILI were not different between PAI-1 gene-deficient and wild-type mice. These data indicate that a defect fibrinolytic response attenuates recruitment of neutrophils in VILI.

Lack of matrix metalloproteinase-9 worsens ventilator-induced lung injury

2008 ◽  
Vol 294 (3) ◽  
pp. L535-L543 ◽  
Author(s):  
Guillermo M. Albaiceta ◽  
Ana Gutiérrez-Fernández ◽  
Diego Parra ◽  
Aurora Astudillo ◽  
Emilio García-Prieto ◽  
...  
Keyword(s):  
Lung Injury ◽  
Matrix Metalloproteinase ◽  
Cell Count ◽  
Matrix Metalloproteinase 9 ◽  
Lung Mechanics ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Ventilator Induced Lung Injury ◽  
Metalloproteinase 9

Matrix metalloproteinase-9 (MMP-9) is released by neutrophils at the sites of acute inflammation. This enzyme modulates matrix turnover and inflammatory response, and its activity has been found to be increased after ventilator-induced lung injury. To clarify the role of MMP-9, mice lacking this enzyme and their wild-type counterparts were ventilated for 2 h with high- or low-peak inspiratory pressures (25 and 15 cmH2O, respectively). Lung injury was evaluated by gas exchange, respiratory mechanics, wet-to-dry weight ratio, and histological analysis. The activity of MMP-9 and levels of IL-1β, IL-4, and macrophage inflammatory protein (MIP-2) were measured in lung tissue and bronchoalveolar lavage fluid (BALF). Cell count and myeloperoxidase activity were measured in BALF. There were no differences between wild-type and Mmp9−/− animals after low-pressure ventilation. After high-pressure ventilation, wild-type mice exhibited an increase in MMP-9 in tissue and BALF. Mice lacking MMP-9 developed more severe lung injury than wild-type mice, in terms of impaired oxygenation and lung mechanics, and higher damage in the histological study. These effects correlated with an increase in both cell count and myeloperoxidase activity in the BALF, suggesting an increased neutrophilic influx in response to ventilation. An increase in IL-1β and IL-4 in the BALF only in knockout mice could be responsible for the differences. There were no differences between genotypes in MMP-2, MMP-8, or tissue inhibitors of metalloproteinases. These results show that MMP-9 protects against ventilator-induced lung injury by decreasing alveolar neutrophilic infiltration, probably by modulation of the cytokine response in the air spaces.

Congenital NOS2 deficiency prevents impairment of hypoxic pulmonary vasoconstriction in murine ventilator-induced lung injury

2007 ◽  
Vol 293 (5) ◽  
pp. L1300-L1305 ◽  
Author(s):  
Rong Liu ◽  
Yukako Hotta ◽  
Amanda R. Graveline ◽  
Oleg V. Evgenov ◽  
Emmanuel S. Buys ◽  
...  
Keyword(s):  
Lung Injury ◽  
Tidal Volume ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Left Lung ◽  
Arterial Oxygen Tension ◽  
Arterial Oxygen ◽  
Lung Edema ◽  
Wild Type ◽  
Ventilator Induced Lung Injury ◽  
Pulmonary Vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) preserves systemic arterial oxygenation during lung injury by diverting blood flow away from poorly ventilated lung regions. Ventilator-induced lung injury (VILI) is characterized by pulmonary inflammation, lung edema, and impaired HPV leading to systemic hypoxemia. Studying mice congenitally deficient in inducible nitric oxide synthase (NOS2) and wild-type mice treated with a selective NOS2 inhibitor, l- N6-(1-iminoethyl)lysine (l-NIL), we investigated the contribution of NOS2 to the impairment of HPV in anesthetized mice subjected to 6 h of either high tidal volume (HVT) or low tidal volume (LVT) ventilation. HPV was estimated by measuring the changes of left lung pulmonary vascular resistance (LPVR) in response to left mainstem bronchus occlusion (LMBO). LMBO increased the LPVR similarly in wild-type, NOS2−/−, and wild-type mice treated with l-NIL 30 min before commencing 6 h of LVT ventilation (96% ± 30%, 103% ± 33%, and 80% ± 16%, respectively, means ± SD). HPV was impaired in wild-type mice subjected to 6 h of HVT ventilation (23% ± 16%). In contrast, HPV was preserved after 6 h of HVT ventilation in NOS2−/− and wild-type mice treated with l-NIL either 30 min before or 6 h after commencing HVT ventilation (66% ± 22%, 82% ± 29%, and 85% ± 16%, respectively). After 6 h of HVT ventilation and LMBO, systemic arterial oxygen tension was higher in NOS2−/− than in wild-type mice (192 ± 11 vs. 171 ± 17 mmHg; P < 0.05). We conclude that either congenital NOS2 deficiency or selective inhibition of NOS2 protects mice from the impairment of HPV occurring after 6 h of HVT ventilation.

scholarly journals Dexamethasone Attenuates VEGF Expression and Inflammation but Not Barrier Dysfunction in a Murine Model of Ventilator–Induced Lung Injury

PLoS ONE ◽  
2013 ◽  
Vol 8 (2) ◽  
pp. e57374 ◽  
Author(s):  
Maria A. Hegeman ◽  
Marije P. Hennus ◽  
Pieter M. Cobelens ◽  
Annemieke Kavelaars ◽  
Nicolaas J. G. Jansen ◽  
...  
Keyword(s):  
Lung Injury ◽  
Murine Model ◽  
Barrier Dysfunction ◽  
Vegf Expression ◽  
Ventilator Induced Lung Injury

scholarly journals MiR-135a Protects Vascular Endothelial Cells Against Ventilator-Induced Lung Injury by Inhibiting PHLPP2 to Activate PI3K/Akt Pathway

2018 ◽  
Vol 48 (3) ◽  
pp. 1245-1258 ◽  
Author(s):  
Xiaodi Yan ◽  
Wenqian Li ◽  
Liye Yang ◽  
Wenwen Dong ◽  
Wei Chen ◽  
...  
Keyword(s):  
Lung Injury ◽  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
Akt Signaling ◽  
Luciferase Reporter ◽  
Apoptotic Cells ◽  
Akt Signaling Pathway ◽  
Barrier Dysfunction ◽  
Over Expression ◽  
Ventilator Induced Lung Injury

Background/Aims: Loss of endothelial barrier function plays an important role in the development of ventilator-induced lung injury (VILI). This study aimed to investigate the effects of miR135a on VILI in a model of mechanical stretch (MS)-induced human umbilical vein endothelial cell (HUVEC) injury. Methods: HUVECs were randomly assigned to 7 groups: blank, negative control (NC), NC+MS, miR135a over-expression (mi-miR135a), mi-miR135a + MS, miR135a silencing (si-miR135a) and si-miR135a + MS groups. MS was induced by subjecting cells to cyclic stretch at 20% stretch for 4 h. After 24 h, levels of reactive oxygen species (ROS) were measured by DCFH-DA fluorescence intensity. Apoptosis was measured using annexin V-FITC/propidium iodide assay with flow cytometry. Inflammatory cytokine levels were determined by ELISA. Barrier integrity was determined using FITC-conjugated dextran assay. Expression levels of PI3K, p-PI3K, Akt, p-Akt, Bcl-2 and Bax were examined using western blotting. The interaction between miR135a and PHLPP2 was evaluated by dual-luciferase reporter assay. Results: Our results showed that MS reduced cell numbers, increased the number of apoptotic cells, increased ROS, barrier dysfunction and inflammatory cytokines in HUVECs, and reduced p-PI3K and p-Akt expression; silencing of miR135a worsened MS-induced HUVEC injury. However, miR135a over-expression protected HUVECs against MS-induced increases in apoptotic cells, ROS, barrier dysfunction and inflammatory cytokines, which were accompanied by activation of the PI3K/Akt signaling pathway. Simultaneous silencing of miR135a and PHLPP2 partially salvaged the effects of miR135a silencing, and miR135a was found to interact with PHLPP2. Conclusion: miR135a may protect HUVECs from MS-induced injury by inhibiting PHLPP2 to activate PI3k/Akt signaling pathway.

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