Interaction between regional lung volumes and ventilator-induced lung injury in the normal and endotoxemic lung

Both overdistension and atelectasis contribute to lung injury and mortality during mechanical ventilation. It has been proposed that combinations of tidal volume and end-expiratory lung volume exist that minimize lung injury linked to mechanical ventilation. The aim of this study was to examine this at the regional level in the healthy and endotoxemic lung. Adult female BALB/c mice were injected intraperitoneally with 10 mg/kg lipopolysaccharide (LPS) in saline or with saline alone. Four hours later, mice were mechanically ventilated for 2 h. Regional specific end-expiratory volume (sEEV) and tidal volume (sVt) were measured at baseline and after 2 h of ventilation using dynamic high-resolution four-dimensional computed tomography images. The regional expression of inflammatory genes was quantified by quantitative PCR. There was a heterogenous response in regional sEEV whereby endotoxemia increased gas trapping at end-expiration in some lung regions. Within the healthy group, there was a relationship between sEEV, sVt, and the expression of Tnfa, where high Vt in combination with high EEV or very low EEV was associated with an increase in gene expression. In endotoxemia there was an association between low sEEV, particularly when this was combined with moderate sVt, and high expression of IL6. Our data suggest that preexisting systemic inflammation modifies the relationship between regional lung volumes and inflammation and that although optimum EEV-Vt combinations to minimize injury exist, further studies are required to identify the critical inflammatory mediators to assess and the effect of different injury types on the response.

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The proteomic response is linked to regional lung volumes in ventilator-induced lung injury

Journal of Applied Physiology ◽

10.1152/japplphysiol.00097.2020 ◽

2020 ◽

Vol 129 (4) ◽

pp. 837-845

Author(s):

Seiha Yen ◽

Yong Song ◽

Melissa Preissner ◽

Ellen Bennett ◽

Richard Wilson ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Complex Interaction ◽

Lung Volumes ◽

Ventilator Induced Lung Injury ◽

Regional Lung ◽

Altered Regulation ◽

Proteomic Response

This study provides novel insights into the regional response to mechanical ventilation in the setting of acid-induced lung injury and highlights the complex interaction between tidal stretch and low end-expiratory lung volumes; both of which caused altered regulation of different injury pathways.

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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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Redox Balance and Cellular Inflammation in the Diaphragm, Limb Muscles, and Lungs of Mechanically Ventilated Rats

Anesthesiology ◽

10.1097/aln.0b013e3181c38bed ◽

2010 ◽

Vol 112 (2) ◽

pp. 384-394 ◽

Cited By ~ 12

Author(s):

Judith Marín-Corral ◽

Leticia Martínez-Caro ◽

José A. Lorente ◽

Marta de Paula ◽

Lara Pijuan ◽

...

Keyword(s):

Oxidative Stress ◽

Mechanical Ventilation ◽

Lung Injury ◽

Protein Adducts ◽

Organ Injury ◽

Mechanically Ventilated ◽

Ventilator Induced Lung Injury ◽

Cellular Inflammation ◽

Cell Counts ◽

Limb Muscles

Background High tidal volume (VT) mechanical ventilation was shown to induce organ injury other than lung injury and systemic inflammation in animal models of ventilator-induced lung injury. The authors aimed to explore whether high VT mechanical ventilation per se induces early oxidative stress and inflammation in the diaphragm, limb muscles, and lungs of healthy rats exposed to ventilator-induced lung injury. Methods Protein carbonylation and nitration, antioxidants (immunoblotting), and inflammation (immunohistochemistry) were evaluated in the diaphragm, gastrocnemius, soleus, tibialis anterior, and lungs of mechanically ventilated healthy rats and in nonventilated control animals (n = 8/group) for 1 h, using two different strategies (moderate VT [VT = 9 ml/kg] and high VT [VT = 35 ml/kg]). Results The main findings are summarized as follows: compared with controls, (1) the diaphragms and gastrocnemius of high-VT rats exhibited a decrease in reactive carbonyls, (2) the soleus and tibialis of high- and moderate-VT rodents showed a reduction in reactive carbonyls and malondialdehyde-protein adducts, (3) the lungs of high-VT rats exhibited a significant rise in malondialdehyde-protein adducts, (4) the soleus and tibialis of both high- and moderate-VT rats showed a reduction in protein nitration, (5) the lungs of high- and moderate-VT rats showed a reduction in antioxidant enzyme levels, but not in the muscles, and (6) the diaphragms and gastrocnemius of all groups exhibited very low inflammatory cell counts, whereas the lungs of high-VT rats exhibited a significant increase in inflammatory infiltrates. Conclusions Although oxidative stress and inflammation increased in the lungs of rats exposed to high VT, the diaphragm and limb muscles exhibited a decline in oxidative stress markers and very low levels of cellular inflammation.

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Inhibition of Poly(Adenosine Diphosphate–Ribose) Polymerase Attenuates Ventilator-induced Lung Injury

Anesthesiology ◽

10.1097/01.anes.0000299434.86640.15 ◽

2008 ◽

Vol 108 (2) ◽

pp. 261-268 ◽

Cited By ~ 37

Author(s):

Rosanna Vaschetto ◽

Jan W. Kuiper ◽

Shyh Ren Chiang ◽

Jack J. Haitsma ◽

Jonathan W. Juco ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Tidal Volume ◽

Interleukin 6 ◽

Inflammatory Responses ◽

Adenosine Diphosphate ◽

High Tidal Volume ◽

Positive End Expiratory Pressure ◽

Ventilator Induced Lung Injury ◽

Pharmacologic Inhibition

Background Mechanical ventilation can induce organ injury associated with overwhelming inflammatory responses. Excessive activation of poly(adenosine diphosphate-ribose) polymerase enzyme after massive DNA damage may aggravate inflammatory responses. Therefore, the authors hypothesized that the pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase by PJ-34 would attenuate ventilator-induced lung injury. Methods Anesthetized rats were subjected to intratracheal instillation of lipopolysaccharide at a dose of 6 mg/kg. The animals were then randomly assigned to receive mechanical ventilation at either low tidal volume (6 ml/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (15 ml/kg) with zero positive end-expiratory pressure, in the presence and absence of intravenous administration of PJ-34. Results The high-tidal-volume ventilation resulted in an increase in poly(adenosine diphosphate-ribose) polymerase activity in the lung. The treatment with PJ-34 maintained a greater oxygenation and a lower airway plateau pressure than the vehicle control group. This was associated with a decreased level of interleukin 6, active plasminogen activator inhibitor 1 in the lung, attenuated leukocyte lung transmigration, and reduced pulmonary edema and apoptosis. The administration of PJ-34 also decreased the systemic levels of tumor necrosis factor alpha and interleukin 6, and attenuated the degree of apoptosis in the kidney. Conclusion The pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase reduces ventilator-induced lung injury and protects kidney function.

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Mechanosensitive cation channel Piezo1 contributes to ventilator-induced lung injury by activating RhoA/ROCK1 in rats

Respiratory Research ◽

10.1186/s12931-021-01844-3 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yang Zhang ◽

Lulu Jiang ◽

Tianfeng Huang ◽

Dahao Lu ◽

Yue Song ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Tidal Volume ◽

Cyclic Stretch ◽

High Tidal Volume ◽

Enzyme Linked Immunosorbent Assay ◽

Sprague Dawley ◽

Ventilator Induced Lung Injury ◽

Enhanced Expression ◽

Underlying Mechanisms

Abstract Background Mechanical ventilation can induce or aggravate lung injury, which is termed ventilator-induced lung injury (VILI). Piezo1 is a key element of the mechanotransduction process and can transduce mechanical signals into biological signals by mediating Ca2+ influx, which in turn regulates cytoskeletal remodeling and stress alterations. We hypothesized that it plays an important role in the occurrence of VILI, and investigated the underlying mechanisms. Methods High tidal volume mechanical ventilation and high magnitude cyclic stretch were performed on Sprague–Dawley rats, and A549 and human pulmonary microvascular endothelial cells, respectively, to establish VILI models. Immunohistochemical staining, flow cytometry, histological examination, enzyme-linked immunosorbent assay, western blotting, quantitative real-time polymerase chain reaction and survival curves were used to assess the effect of Piezo1 on induction of lung injury, as well as the signaling pathways involved. Results We observed that Piezo1 expression increased in the lungs after high tidal volume mechanical ventilation and in cyclic stretch-treated cells. Mechanistically, we observed the enhanced expression of RhoA/ROCK1 in both cyclic stretch and Yoda1-treated cells, while the deficiency or inhibition of Piezo1 dramatically antagonized RhoA/ROCK1 expression. Furthermore, blockade of RhoA/ROCK1 signaling using an inhibitor did not affect Piezo1 expression. GSMTx4 was used to inhibit Piezo1, which alleviated VILI-induced pathologic changes, water content and protein leakage in the lungs, and the induction of systemic inflammatory mediators, and improved the 7-day mortality rate in the model rats. Conclusions These findings indicate that Piezo1 affects the development and progression of VILI through promotion of RhoA/ROCK1 signaling.

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The Extent of Ventilator-Induced Lung Injury in Mice Partly Depends on Duration of Mechanical Ventilation

Critical Care Research and Practice ◽

10.1155/2013/435236 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Maria A. Hegeman ◽

Sabrine N. T. Hemmes ◽

Maria T. Kuipers ◽

Lieuwe D. J. Bos ◽

Geartsje Jongsma ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Capillary Permeability ◽

Statistical Significance ◽

Lung Compliance ◽

Alveolar Cell ◽

Mechanically Ventilated ◽

Ventilator Induced Lung Injury ◽

Cell Counts ◽

Alveolar Capillary

Background. Mechanical ventilation (MV) has the potential to initiate ventilator-induced lung injury (VILI). The pathogenesis of VILI has been primarily studied in animal models using more or less injurious ventilator settings. However, we speculate that duration of MV also influences severity and character of VILI.Methods. Sixty-four healthy C57Bl/6 mice were mechanically ventilated for 5 or 12 hours, using lower tidal volumes with positive end-expiratory pressure (PEEP) or higher tidal volumes without PEEP. Fifteen nonventilated mice served as controls.Results. All animals remained hemodynamically stable and survived MV protocols. In both MV groups, PaO2to FiO2ratios were lower and alveolar cell counts were higher after 12 hours of MV compared to 5 hours. Alveolar-capillary permeability was increased after 12 hours compared to 5 hours, although differences did not reach statistical significance. Lung levels of inflammatory mediators did not further increase over time. Only in mice ventilated with increased strain, lung compliance declined and wet to dry ratio increased after 12 hours of MV compared to 5 hours.Conclusions. Deleterious effects of MV are partly dependent on its duration. Even lower tidal volumes with PEEP may initiate aspects of VILI after 12 hours of MV.

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Mechanical Ventilation and the Titer of Antibodies as Risk Factors for the Development of Transfusion-Related Lung Injury

Critical Care Research and Practice ◽

10.1155/2012/720950 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

A. P. J. Vlaar ◽

M. T. Kuipers ◽

J. J. Hofstra ◽

E. K. Wolthuis ◽

C. W. Wieland ◽

...

Keyword(s):

Risk Factors ◽

Mechanical Ventilation ◽

Acute Lung Injury ◽

Lung Injury ◽

Tidal Volume ◽

Event Data ◽

Combined Model ◽

Mhc I ◽

Neutrophil Influx ◽

Ventilator Induced Lung Injury

Purpose. Onset of transfusion-related acute lung injury (TRALI) is suggested to be a threshold-event. Data is lacking on the relation between titer of antibodies infused and onset of TRALI. We determined whether onset of TRALI is dependent on the titer of MHC-I antibodies infused in a combined model of ventilator-induced lung injury and antibody-induced TRALl.Methods. BALB/c mice were ventilated for five hours with low (7.5 ml/kg) or high (15 ml/kg) tidal volume. After three hours of MV, TRALI was induced by infusion of 0.5 mg/kg, 2.0 mg/kg or 4.5 mg/kg MHC-I antibodies. Control animals received vehicle. After five hours of MV, animals were sacrificed.Results. MV with high tidal volumes resulted in increased levels of all markers of lung injury compared to animals ventilated with low tidal MV. In ventilator-induced lung injury, infusion of 4.5 mg/kg of antibodies further increased pulmonary wet-to-dry ratio, pulmonary neutrophil influx and pulmonary KC levels, whereas infusion of lower dose of antibodies did not augment lung injury. In contrast, mice ventilated with low tidal volumes did not develop lung injury, irrespective of the dose of antibody used.Conclusions. In the presence of injurious MV, onset of TRALI depends on the titer of antibodies infused.

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Activation of calpains mediates early lung neutrophilic inflammation in ventilator-induced lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00349.2011 ◽

2012 ◽

Vol 302 (4) ◽

pp. L370-L379 ◽

Cited By ~ 24

Author(s):

Dejie Liu ◽

Zhibo Yan ◽

Richard D. Minshall ◽

David E. Schwartz ◽

Yuguo Chen ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Tidal Volume ◽

Lung Inflammation ◽

Inflammatory Responses ◽

Neutrophil Recruitment ◽

Calpain Activation ◽

Ventilator Induced Lung Injury ◽

Volume Ventilation ◽

Calpain 2

Lung inflammatory responses in the absence of infection are considered to be one of primary mechanisms of ventilator-induced lung injury. Here, we determined the role of calpain in the pathogenesis of lung inflammation attributable to mechanical ventilation. Male C57BL/6J mice were subjected to high (28 ml/kg) tidal volume ventilation for 2 h in the absence and presence of calpain inhibitor I (10 mg/kg). To address the isoform-specific functions of calpain 1 and calpain 2 during mechanical ventilation, we utilized a liposome-based delivery system to introduce small interfering RNAs targeting each isoform in pulmonary vasculature in vivo. Mechanical ventilation with high tidal volume induced rapid (within minutes) and persistent calpain activation and lung inflammation as evidenced by neutrophil recruitment, production of TNF-α and IL-6, pulmonary vascular hyperpermeability, and lung edema formation. Pharmaceutical calpain inhibition significantly attenuated these inflammatory responses caused by lung hyperinflation. Depletion of calpain 1 or calpain 2 had a protective effect against ventilator-induced lung inflammatory responses. Inhibition of calpain activity by means of siRNA silencing or pharmacological inhibition also reduced endothelial nitric oxide (NO) synthase (NOS-3)-mediated NO production and subsequent ICAM-1 phosphorylation following high tidal volume ventilation. These results suggest that calpain activation mediates early lung inflammation during ventilator-induced lung injury via NOS-3/NO-dependent ICAM-1 phosphorylation and neutrophil recruitment. Inhibition of calpain activation may therefore provide a novel and promising strategy for the prevention and treatment of ventilator-induced lung injury.

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Chronic lung injury in preterm lambs: disordered pulmonary elastin deposition

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1997.272.3.l452 ◽

1997 ◽

Vol 272 (3) ◽

pp. L452-L460 ◽

Cited By ~ 44

Author(s):

R. A. Pierce ◽

K. H. Albertine ◽

B. C. Starcher ◽

J. F. Bohnsack ◽

D. P. Carlton ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Tidal Volume ◽

Mrna Expression ◽

Lung Tissue ◽

Prolonged Mechanical Ventilation ◽

Morphological Development ◽

Mechanically Ventilated ◽

Alveolar Development

Prolonged mechanical ventilation of premature neonates is often associated with abnormal morphological development of the lung and chronic lung disease, sometimes called bronchopulmonary dysplasia (BPD). Impaired alveolar development is a hallmark of this disease. To better understand the effects of mechanical ventilation on lung elastin expression, we studied lung tissue from 10 preterm lambs (gestation = 125 days; term = 148 days) mechanically ventilated for 3-4 wk at a respirator rate of 20 breaths/min and tidal volume of 15 +/- 5 ml/kg (n = 5) or 60 breaths/min and tidal volume of 5 +/- 2 ml/kg (n = 5). Histopathology showed increased elastin accumulation and abnormal morphological development in the ventilated groups. Postmortem lung desmosine content was increased significantly in the 20 breaths/min group. Tropoelastin mRNA expression was increased in both ventilated groups. In situ hybridization localized increased tropoelastin mRNA expression to sites of accumulated elastin in extended alveolar walls with scant, attenuated secondary crests. Lung collagen content, as assessed by the amount of hydroxyproline in lung tissue, was similar to controls. These data suggest that excessive production and accumulation of elastin is associated with chronic lung injury from prolonged mechanical ventilation after premature birth.

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Alveolar macrophages contribute to alveolar barrier dysfunction in ventilator-induced lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00055.2006 ◽

2006 ◽

Vol 291 (6) ◽

pp. L1191-L1198 ◽

Cited By ~ 104

Author(s):

James A. Frank ◽

Charlie M. Wray ◽

Danny F. McAuley ◽

Reto Schwendener ◽

Michael A. Matthay

Keyword(s):

Mechanical Ventilation ◽

Epithelial Cell ◽

Lung Injury ◽

Tidal Volume ◽

Alveolar Macrophage ◽

Alveolar Macrophages ◽

Macrophage Activation ◽

Alveolar Epithelial Cell ◽

Alveolar Epithelial ◽

Ventilator Induced Lung Injury

In patients requiring mechanical ventilation for acute lung injury or acute respiratory distress syndrome (ARDS), tidal volume reduction decreases mortality, but the mechanisms of the protective effect have not been fully explored. To test the hypothesis that alveolar macrophage activation is an early and critical event in the initiation of ventilator-induced lung injury (VILI), rats were ventilated with high tidal volume (HVT) for 10 min to 4 h. Alveolar macrophage counts in bronchoalveolar lavage (BAL) fluid decreased 45% by 20 min of HVT( P < 0.05) consistent with activation-associated adhesion. Depletion of alveolar macrophages in vivo with liposomal clodronate significantly decreased permeability and pulmonary edema following 4 h of HVT( P < 0.05). BAL fluid from rats exposed to 20 min of HVTincreased nitric oxide synthase activity nearly threefold in naïve primary alveolar macrophages ( P < 0.05) indicating that soluble factors present in the air spaces contribute to macrophage activation in VILI. Media from cocultures of alveolar epithelial cell monolayers and alveolar macrophages exposed to 30 min of stretch in vitro also significantly increased nitrite production in naïve macrophages ( P < 0.05), but media from stretched alveolar epithelial cells or primary alveolar macrophages alone did not, suggesting alveolar epithelial cell-macrophage interaction was required for the subsequent macrophage activation observed. These data demonstrate that injurious mechanical ventilation rapidly activates alveolar macrophages and that alveolar macrophages play an important role in the initial pathogenesis of VILI.

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