T2 Blockade of intraalveolar p55 TNF-receptor signalling by a domain antibody decreases inflammation and oedema in an in vivo mouse model of ventilator-induced lung injury

Mechanical ventilation has been demonstrated to exacerbate lung injury, and a sufficiently high tidal volume can induce injury in otherwise healthy lungs. However, it remains controversial whether injurious ventilation per se, without preceding lung injury, can initiate cytokine-mediated pulmonary inflammation. To address this, we developed an in vivo mouse model of acute lung injury produced by high tidal volume (Vt) ventilation. Anesthetized C57BL6 mice were ventilated at high Vt (34.5 ± 2.9 ml/kg, mean ± SD) for a duration of 156 ± 17 min until mean blood pressure fell below 45 mmHg ( series 1); high Vt for 120 min ( series 2); or low Vt (8.8 ± 0.5 ml/kg) for 120 or 180 min ( series 3). High Vt produced progressive lung injury with a decrease in respiratory system compliance, increase in protein concentration in lung lavage fluid, and lung pathology showing hyaline membrane formation. High-Vt ventilation was associated with increased TNF-α in lung lavage fluid at the early stage of injury ( series 2) but not the later stage ( series 1). In contrast, lavage fluid macrophage inflammatory protein-2 (MIP-2) was increased in all high-Vt animals. Lavage fluid from high-Vt animals contained bioactive TNF-α by WEHI bioassay. Low-Vt ventilation induced minimal changes in physiology and pathology with negligible TNF-α and MIP-2 proteins and TNF-α bioactivity. These results demonstrate that high-Vt ventilation in the absence of underlying injury induces intrapulmonary TNF-α and MIP-2 expression in mice. The apparently transient nature of TNF-α upregulation may help explain previous controversy regarding the involvement of cytokines in ventilator-induced lung injury.

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Magnetic resonance imaging provides sensitive in vivo assessment of experimental ventilator-induced lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00459.2015 ◽

2016 ◽

Vol 311 (2) ◽

pp. L208-L218 ◽

Cited By ~ 8

Author(s):

Dean O. Kuethe ◽

Piotr T. Filipczak ◽

Jeremy M. Hix ◽

Andrew P. Gigliotti ◽

Raúl San José Estépar ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Lung Injury ◽

Real Time ◽

Critical Role ◽

Lung Mechanics ◽

Therapeutic Effects ◽

Resonance Imaging ◽

Ventilator Induced Lung Injury

Animal models play a critical role in the study of acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI). One limitation has been the lack of a suitable method for serial assessment of acute lung injury (ALI) in vivo. In this study, we demonstrate the sensitivity of magnetic resonance imaging (MRI) to assess ALI in real time in rat models of VILI. Sprague-Dawley rats were untreated or treated with intratracheal lipopolysaccharide or PBS. After 48 h, animals were mechanically ventilated for up to 15 h to induce VILI. Free induction decay (FID)-projection images were made hourly. Image data were collected continuously for 30 min and divided into 13 phases of the ventilatory cycle to make cinematic images. Interleaved measurements of respiratory mechanics were performed using a flexiVent ventilator. The degree of lung infiltration was quantified in serial images throughout the progression or resolution of VILI. MRI detected VILI significantly earlier (3.8 ± 1.6 h) than it was detected by altered lung mechanics (9.5 ± 3.9 h, P = 0.0156). Animals with VILI had a significant increase in the Index of Infiltration ( P = 0.0027), and early regional lung infiltrates detected by MRI correlated with edema and inflammatory lung injury on histopathology. We were also able to visualize and quantify regression of VILI in real time upon institution of protective mechanical ventilation. Magnetic resonance lung imaging can be utilized to investigate mechanisms underlying the development and propagation of ALI, and to test the therapeutic effects of new treatments and ventilator strategies on the resolution of ALI.

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CYCLIN-DEPENDENT KINASE INHIBITION REDUCES LUNG DAMAGE IN A MOUSE MODEL OF VENTILATOR-INDUCED LUNG INJURY

Shock ◽

10.1097/shk.0b013e3182656e7b ◽

2012 ◽

Vol 38 (4) ◽

pp. 375-380 ◽

Cited By ~ 9

Author(s):

Arie J. Hoogendijk ◽

Maria T. Kuipers ◽

Tom van der Poll ◽

Marcus J. Schultz ◽

Catharina W. Wieland

Keyword(s):

Lung Injury ◽

Mouse Model ◽

Lung Damage ◽

Cyclin Dependent Kinase ◽

Kinase Inhibition ◽

Ventilator Induced Lung Injury

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ID: 60: ZINC DEFICIENCY PRIMES THE LUNG FOR VENTILATOR INDUCED LUNG INJURY

Journal of Investigative Medicine ◽

10.1136/jim-2016-000120.129 ◽

2016 ◽

Vol 64 (4) ◽

pp. 973.1-973

Author(s):

J Englert ◽

F Boudreault ◽

M Pinilla-Vera ◽

C Isabelle ◽

A Arciniegas ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Zinc Deficiency ◽

Zinc Homeostasis ◽

Adaptive Responses ◽

Ventilator Induced Lung Injury ◽

Human Lung Cells ◽

Zinc Levels ◽

Cellular Zinc

Mechanical ventilation is a necessary intervention to support patients with lung injury and the acute respiratory distress syndrome (ARDS), but can also exacerbate injury through mechanical stress-activated signaling pathways. We show that stretch applied to cultured human lung cells, and to mouse lungs in vivo, induces robust expression of metallothionein, a potent anti-oxidant and cyto-protective molecule critical for cellular zinc homeostasis. Furthermore, genetic deficiency of murine metallothionein genes exacerbated lung injury caused by injurious mechanical ventilation, identifying an adaptive role for these genes in limiting lung injury. Stretch induction of metallothionein required zinc and the zinc binding transcription factor MTF-1. We further show that dietary zinc-deficiency in mice potentiates ventilator-induced lung injury, and that plasma zinc levels are significantly reduced in human patients with ARDS compared to healthy and non-ARDS ICU controls, as well as to other critically ill patients without ARDS. Taken together, our findings identify a novel adaptive response of the lung to stretch mediated by metallothionein and zinc. These results demonstrate that failure of stretch-adaptive responses play an important role in exacerbating ventilator-induced lung injury, and identify zinc and metallothionein as targets for developing lung-protective interventions in patients requiring mechanical ventilation.

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Inhibition of TNF Receptor p55 By a Domain Antibody Attenuates the Initial Phase of Acid-Induced Lung Injury in Mice

Frontiers in Immunology ◽

10.3389/fimmu.2017.00128 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 10

Author(s):

Michael R. Wilson ◽

Kenji Wakabayashi ◽

Szabolcs Bertok ◽

Charlotte M. Oakley ◽

Brijesh V. Patel ◽

...

Keyword(s):

Lung Injury ◽

Initial Phase ◽

Tnf Receptor ◽

Domain Antibody

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Vascular Remodeling Protects against Ventilator-induced Lung Injury in the In Vivo Rat

Anesthesiology ◽

10.1097/aln.0b013e318173ed20 ◽

2008 ◽

Vol 108 (6) ◽

pp. 1047-1054 ◽

Cited By ~ 4

Author(s):

Alik Kornecki ◽

Doreen Engelberts ◽

Patrick McNamara ◽

Robert P. Jankov ◽

Conán McCaul ◽

...

Keyword(s):

Electron Microscopy ◽

Pulmonary Hypertension ◽

Lung Injury ◽

Vascular Remodeling ◽

Kinase Inhibitor ◽

Lung Mechanics ◽

Pulmonary Vasculature ◽

Ventilator Induced Lung Injury ◽

Chronic Pulmonary Hypertension

Background The role of the pulmonary vasculature in the pathogenesis of ventilator-induced lung injury is not well established. In this study, the authors investigated the effect of vascular remodeling due to chronic pulmonary hypertension on susceptibility to ventilator-induced lung injury. The authors hypothesized that the enhanced vascular tensile strength associated with pulmonary vascular remodeling would protect against ventilator-induced lung injury. Methods Chronic pulmonary arterial hypertension was induced in rats by exposure to hypoxia for 28 days and was confirmed by demonstration of right ventricular hypertrophy. Normotensive and hypertensive groups of rats (as well as a group in which pulmonary hypertension was acutely reversed with a Rho-kinase inhibitor, Y-27632) were exposed to injurious ventilation (respiratory rate 30 min, 30/0 cm H2O) for 90 min. Lung injury was assessed by change in lung mechanics, oxygenation, edema development, and cytokine levels. Electron microscopy was used to examine vascular structure in additional animals. Results Injurious ventilation caused significant lung injury (lung compliance, oxygenation, pulmonary edema) in the normotensive controls, but not in the presence of pulmonary hypertension; acute reversal of pulmonary hypertension did not alter the lessened susceptibility to ventilator-induced lung injury. Electron microscopy demonstrated capillary endothelial and epithelial breaks in injuriously ventilated normotensive controls that were not seen with pulmonary hypertension, whether or not the pulmonary hypertension was acutely reversed. Conclusions Vascular remodeling induced by chronic pulmonary hypertension confers protection against the effects of injurious mechanical ventilation in vivo by a mechanism that may involve structural alterations rather than increased pulmonary artery pressure.

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Ventilator-induced lung-injury in mouse models: Is there a trap?

Laboratory Animal Research ◽

10.1186/s42826-021-00108-x ◽

2021 ◽

Vol 37 (1) ◽

Author(s):

Jon Petur Joelsson ◽

Saevar Ingthorsson ◽

Jennifer Kricker ◽

Thorarinn Gudjonsson ◽

Sigurbergur Karason

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Mouse Models ◽

Mechanical Strain ◽

Acute Injury ◽

In Vivo Studies ◽

Cellular Interactions ◽

Ventilator Induced Lung Injury

AbstractVentilator-induced lung injury (VILI) is a serious acute injury to the lung tissue that can develop during mechanical ventilation of patients. Due to the mechanical strain of ventilation, damage can occur in the bronchiolar and alveolar epithelium resulting in a cascade of events that may be fatal to the patients. Patients requiring mechanical ventilation are often critically ill, which limits the possibility of obtaining patient samples, making VILI research challenging. In vitro models are very important for VILI research, but the complexity of the cellular interactions in multi-organ animals, necessitates in vivo studies where the mouse model is a common choice. However, the settings and duration of ventilation used to create VILI in mice vary greatly, causing uncertainty in interpretation and comparison of results. This review examines approaches to induce VILI in mouse models for the last 10 years, to our best knowledge, summarizing methods and key parameters presented across the studies. The results imply that a more standardized approach is warranted.

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Experimental Ventilator-induced Lung Injury

Anesthesiology ◽

10.1097/aln.0b013e31819fcba9 ◽

2009 ◽

Vol 110 (6) ◽

pp. 1341-1347 ◽

Cited By ~ 27

Author(s):

Jesús Villar ◽

Maria Teresa Herrera-Abreu ◽

Francisco Valladares ◽

Mercedes Muros ◽

Lina Pérez-Méndez ◽

...

Keyword(s):

Lung Injury ◽

Fatal Outcome ◽

Experimental Studies ◽

Lung Damage ◽

Cytokine Gene Expression ◽

High Peep ◽

Necrosis Factor Alpha ◽

Ventilator Induced Lung Injury ◽

Airway Pressures

Background Previous experimental studies of ventilator-induced lung injury have shown that positive end-expiratory pressure (PEEP) is protective. The authors hypothesized that the application of PEEP during volume-controlled ventilation with a moderately high tidal volume (VT) in previously healthy in vivo rats does not attenuate ventilator-induced lung injury if the peak airway pressure markedly increases during the application of PEEP. Methods Sixty healthy, male Sprague-Dawley rats were anesthetized and randomized to be mechanically ventilated for 4 h at (1) VT of 6 ml/kg, (2) VT of 20 ml/kg, or (3) VT of 20 ml/kg plus 10 cm H2O of PEEP. Peak airway pressures, gas exchange, histologic evaluation, mortality, total lung tissue cytokine gene expression, and serum cytokine concentrations were analyzed. Results Peak airway pressures exceeded 30 cm H2O with high VT plus PEEP. All lungs ventilated with high VT had perivascular edema and inflammatory infiltrates. In addition, those ventilated with PEEP had small hemorrhages foci. Five animals from the high VT plus PEEP group died (P = 0.020). Animals ventilated with high VT (with or without PEEP) had a substantial increase in serum interleukin-6 (P = 0.0002), and those ventilated with high VT plus PEEP had a 5.5-fold increase in systemic levels of tumor necrosis factor-alpha (P = 0.007). Conclusions In contrast to previous reports, PEEP exacerbated lung damage and contributed to fatal outcome in an in vivo, mild overdistension model of ventilator-induced lung injury in previously healthy rats. That is, the addition of high PEEP to a constant large VT causes injury in previously healthy animals.

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Adipose-derived exosomes protect the pulmonary endothelial barrier in ventilator-induced lung injury by inhibiting the TRPV4/Ca2+ signaling pathway

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00255.2019 ◽

2020 ◽

Vol 318 (4) ◽

pp. L723-L741 ◽

Cited By ~ 6

Author(s):

Qian Yu ◽

Daoxin Wang ◽

Xiaoting Wen ◽

Xumao Tang ◽

Di Qi ◽

...

Keyword(s):

Lung Injury ◽

Inflammatory Response ◽

Transient Receptor Potential ◽

Inflammatory Responses ◽

Endothelial Barrier ◽

Mouse Serum ◽

Transient Receptor Potential Vanilloid ◽

Ventilator Induced Lung Injury

Mechanical ventilation (MV) is the main supportive treatment of acute respiratory distress syndrome (ARDS), but it may lead to ventilator-induced lung injury (VILI). Large epidemiological studies have found that obesity was associated with lower mortality in mechanically ventilated patients with acute lung injury, which is known as “obesity paradox.” However, the effects of obesity on VILI are unknown. In the present study, wild-type mice were fed a high-fat diet (HFD) and ventilated with high tidal volume to investigate the effects of obesity on VILI in vivo, and pulmonary microvascular endothelial cells (PMVECs) were subjected to 18% cyclic stretching (CS) to further investigate its underlying mechanism in vitro. We found that HFD protects mice from VILI by alleviating the pulmonary endothelial barrier injury and inflammatory responses in mice. Adipose-derived exosomes can regulate distant tissues as novel adipokines, providing a new mechanism for cell-cell interactions. We extracted three adipose-derived exosomes, including HFD mouse serum exosome (S-Exo), adipose tissue exosome (AT-Exo), and adipose-derived stem cell exosome (ADSC-Exo), and further explored their effects on MV or 18% CS-induced VILI in vivo and in vitro. Administration of three exosomes protected against VILI by suppressing pulmonary endothelial barrier hyperpermeability, repairing the expression of adherens junctions, and alleviating inflammatory response in vivo and in vitro, accompanied by transient receptor potential vanilloid 4 (TRPV4)/Ca2+ pathway inhibition. Collectively, these data indicated that HFD-induced obesity plays a protective role in VILI by alleviating the pulmonary endothelial barrier injury and inflammatory response via adipose-derived exosomes, at least partially, through inhibiting the TRPV4/Ca2+ pathway.

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