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

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.

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Absence Of Cyclooxygenase (COX)-2 Leads To Alveolar Epithelial Barrier Dysfunction And Decreased Expression Of Tight Junction Proteins In A Dual Injury Model Of Polymicrobial Sepsis And Ventilator-Induced Lung Injury

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a2107 ◽

2012 ◽

Author(s):

Margarita M. Suarez Velandia ◽

Jun Ma ◽

Laura E. Fredenburgh

Keyword(s):

Lung Injury ◽

Epithelial Barrier ◽

Tight Junction Proteins ◽

Barrier Dysfunction ◽

Alveolar Epithelial ◽

Ventilator Induced Lung Injury ◽

Injury Model ◽

Cox 2 ◽

Epithelial Barrier Dysfunction ◽

Junction Proteins

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Pre-treatment with dexamethasone attenuates experimental ventilator-induced lung injury

Jornal Brasileiro de Pneumologia ◽

10.1590/s1806-37562015000000350 ◽

2016 ◽

Vol 42 (3) ◽

pp. 166-173 ◽

Cited By ~ 1

Author(s):

Fernando Fonseca dos Reis ◽

Maycon de Moura Reboredo ◽

Leda Marília Fonseca Lucinda ◽

Aydra Mendes Almeida Bianchi ◽

Maria Aparecida Esteves Rabelo ◽

...

Keyword(s):

Lung Injury ◽

Wistar Rats ◽

Sham Group ◽

Saline Control ◽

Control Group ◽

Ventilator Induced Lung Injury ◽

Arterial Blood ◽

Cell Counts ◽

Dexamethasone Group ◽

Pre Treatment

ABSTRACT Objective: To evaluate the effects that administering dexamethasone before the induction of ventilator-induced lung injury (VILI) has on the temporal evolution of that injury. Methods: Wistar rats were allocated to one of three groups: pre-VILI administration of dexamethasone (dexamethasone group); pre-VILI administration of saline (control group); or ventilation only (sham group). The VILI was induced by ventilation at a high tidal volume. Animals in the dexamethasone and control groups were euthanized at 0, 4, 24, and 168 h after VILI induction. We analyzed arterial blood gases, lung edema, cell counts (total and differential) in the BAL fluid, and lung histology. Results: At 0, 4, and 24 h after VILI induction, acute lung injury (ALI) scores were higher in the control group than in the sham group (p < 0.05). Administration of dexamethasone prior to VILI induction decreased the severity of the lung injury. At 4 h and 24 h after induction, the ALI score in the dexamethasone group was not significantly different from that observed for the sham group and was lower than that observed for the control group (p < 0.05). Neutrophil counts in BAL fluid were increased in the control and dexamethasone groups, peaking at 4 h after VILI induction (p < 0.05). However, the neutrophil counts were lower in the dexamethasone group than in the control group at 4 h and 24 h after induction (p < 0.05). Pre-treatment with dexamethasone also prevented the post-induction oxygenation impairment seen in the control group. Conclusions: Administration of dexamethasone prior to VILI induction attenuates the effects of the injury in Wistar rats. The molecular mechanisms of such injury and the possible clinical role of corticosteroids in VILI have yet to be elucidated.

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Pre-treatment with mesenchymal stem cells reduces ventilator-induced lung injury

European Respiratory Journal ◽

10.1183/09031936.00153211 ◽

2012 ◽

Vol 40 (4) ◽

pp. 939-948 ◽

Cited By ~ 34

Author(s):

Laura Chimenti ◽

Tomás Luque ◽

Maria R. Bonsignore ◽

José Ramírez ◽

Daniel Navajas ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Lung Injury ◽

Ventilator Induced Lung Injury ◽

Pre Treatment

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

PLoS ONE ◽

10.1371/journal.pone.0057374 ◽

2013 ◽

Vol 8 (2) ◽

pp. e57374 ◽

Cited By ~ 18

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

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

Cellular Physiology and Biochemistry ◽

10.1159/000492010 ◽

2018 ◽

Vol 48 (3) ◽

pp. 1245-1258 ◽

Cited By ~ 14

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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Cyclic stretch induces alveolar epithelial barrier dysfunction via calpain-mediated degradation of p120-catenin

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00048.2011 ◽

2011 ◽

Vol 301 (2) ◽

pp. L197-L206 ◽

Cited By ~ 28

Author(s):

Yuelan Wang ◽

Richard D. Minshall ◽

David E. Schwartz ◽

Guochang Hu

Keyword(s):

Lung Injury ◽

Alveolar Epithelial Cells ◽

Cyclic Stretch ◽

Epithelial Barrier ◽

Gap Formation ◽

Barrier Dysfunction ◽

P120 Catenin ◽

Alveolar Epithelial ◽

Ventilator Induced Lung Injury ◽

Epithelial Barrier Dysfunction

Lung hyperinflation is known to be an important contributing factor in the pathogenesis of ventilator-induced lung injury. Mechanical stretch causes epithelial barrier dysfunction and an increase in alveolar permeability, although the precise mechanisms have not been completely elucidated. p120-catenin is an adherens junction-associated protein that regulates cell-cell adhesion. In this study, we determined the role of p120-catenin in cyclic stretch-induced alveolar epithelial barrier dysfunction. Cultured alveolar epithelial cells (MLE-12) were subjected to uniform cyclic (0.5 Hz) biaxial stretch from 0 to 8 or 20% change in surface area for 0, 1, 2, or 4 h. At the end of the experiments, cells were lysed to determine p120-catenin expression by Western blot analysis. Immunofluorescence staining of p120-catenin and F-actin was performed to assess the integrity of monolayers and interepithelial gap formation. Compared with unstretched control cells, 20% stretch caused a significant loss in p120-catenin expression, which was coupled to interepithelial gap formation. p120-Catenin knockdown with small interfering RNA (siRNA) dose dependently increased stretch-induced gap formation, whereas overexpression of p120-catenin abolished stretch-induced gap formation. Furthermore, pharmacological calpain inhibition or depletion of calpain-1 with a specific siRNA prevented p120-catenin loss and subsequent stretch-induced gap formation. Our findings demonstrate that p120-catenin plays a critical protective role in cyclic stretch-induced alveolar barrier dysfunction, and, thus, maintenance of p120-catenin expression may be a novel therapeutic strategy for the prevention and treatment of ventilator-induced lung injury.

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Imaging atelectrauma in Ventilator-Induced Lung Injury using 4D X-ray microscopy

Scientific Reports ◽

10.1038/s41598-020-77300-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Luca Fardin ◽

Ludovic Broche ◽

Goran Lovric ◽

Alberto Mittone ◽

Olivier Stephanov ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Lung Parenchyma ◽

Contrast Imaging ◽

Barrier Dysfunction ◽

Mechanically Ventilated ◽

Ventilator Induced Lung Injury ◽

Regional Lung ◽

Ventilation Strategies ◽

Protective Mechanical Ventilation

AbstractMechanical ventilation can damage the lungs, a condition called Ventilator-Induced Lung Injury (VILI). However, the mechanisms leading to VILI at the microscopic scale remain poorly understood. Here we investigated the within-tidal dynamics of cyclic recruitment/derecruitment (R/D) using synchrotron radiation phase-contrast imaging (PCI), and the relation between R/D and cell infiltration, in a model of Acute Respiratory Distress Syndrome in 6 anaesthetized and mechanically ventilated New-Zealand White rabbits. Dynamic PCI was performed at 22.6 µm voxel size, under protective mechanical ventilation [tidal volume: 6 ml/kg; positive end-expiratory pressure (PEEP): 5 cmH2O]. Videos and quantitative maps of within-tidal R/D showed that injury propagated outwards from non-aerated regions towards adjacent regions where cyclic R/D was present. R/D of peripheral airspaces was both pressure and time-dependent, occurring throughout the respiratory cycle with significant scatter of opening/closing pressures. There was a significant association between R/D and regional lung cellular infiltration (p = 0.04) suggesting that tidal R/D of the lung parenchyma may contribute to regional lung inflammation or capillary-alveolar barrier dysfunction and to the progression of lung injury. PEEP may not fully mitigate this phenomenon even at high levels. Ventilation strategies utilizing the time-dependence of R/D may be helpful in reducing R/D and associated injury.

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