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      The differential effects of inspiratory, expiratory, and combined resistive breathing on healthy lung

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          Combined resistive breathing (CRB) is the hallmark of obstructive airway disease pathophysiology. We have previously shown that severe inspiratory resistive breathing (IRB) induces acute lung injury in healthy rats. The role of expiratory resistance is unknown. The possibility of a load-dependent type of resistive breathing-induced lung injury also remains elusive. Our aim was to investigate the differential effects of IRB, expiratory resistive breathing (ERB), and CRB on healthy rat lung and establish the lowest loads required to induce injury. Anesthetized tracheostomized rats breathed through a two-way valve. Varying resistances were connected to the inspiratory, expiratory, or both ports, so that the peak inspiratory pressure (IRB) was 20%–40% or peak expiratory (ERB) was 40%–70% of maximum. CRB was assessed in inspiratory/expiratory pressures of 30%/50%, 40%/50%, and 40%/60% of maximum. Quietly breathing animals served as controls. At 6 hours, respiratory system mechanics were measured, and bronchoalveolar lavage was performed for measurement of cell and protein concentration. Lung tissue interleukin-6 and interleukin-1β levels were estimated, and a lung injury histological score was determined. ERB produced significant, load-independent neutrophilia, without mechanical or permeability derangements. IRB 30% was the lowest inspiratory load that provoked lung injury. CRB increased tissue elasticity, bronchoalveolar lavage total cell, macrophage and neutrophil counts, protein and cytokine levels, and lung injury score in a dose-dependent manner. In conclusion, CRB load dependently deranges mechanics, increases permeability, and induces inflammation in healthy rats. ERB is a putative inflammatory stimulus for the lung.

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          Most cited references 51

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          Experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures. Protection by positive end-expiratory pressure.

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            Ventilation-induced chemokine and cytokine release is associated with activation of nuclear factor-kappaB and is blocked by steroids.

            Recent clinical trials have shown that the survival of patients with acute respiratory distress syndrome (ARDS) is improved by ventilation with reduced volumes. These studies suggested that overinflation of the lungs causes overactivation of the immune system. The present study investigated the hypothesis that ventilation with increased tidal volumes results in early responses similar to those caused by stimulation with one of the major risk factors for ARDS: bacterial lipopolysaccharide (LPS). We therefore compared the effects of ventilation (-10 cm H2O or -25 cm H2O end-inspiratory pressure) and LPS (50 microg/ml) on nuclear factor (NF)-kappaB activation, chemokine release, and cytokine release in isolated perfused lungs obtained from BALB/C mice. We found that both LPS and ventilation with -25 cm H2O (overventilation; OV) caused translocation of NF-kappaB, which was abolished by pretreatment with the steroid dexamethasone. Furthermore, both treatments resulted in similar increases in perfusate levels of alpha-chemokines (macrophage inflammatory protein; [MIP]-2; KC), beta-chemokines (macrophage chemotactic protein-1; MIP-1alpha), and cytokines (tumor necrosis factor-alpha, interleukin-6), which were largely prevented by dexamethasone pretreatment. In LPS-resistant C3H/HeJ mice, only OV, and not LPS, caused translocation of NF-kappaB and release of MIP-2. We conclude that OV evokes early inflammatory responses similar to those evoked by LPS (i.e., NF-kappaB translocation and release of proinflammatory mediators). The NF-kappaB translocation elicited by OV appears to be independent of Toll-like receptor 4 and not due to LPS contamination introduced by the ventilator. Our data further suggest that steroids might be considered as a subsidiary treatment during artificial mechanical ventilation.
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              Mechanisms of surface-tension-induced epithelial cell damage in a model of pulmonary airway reopening.

               D P Gaver,  K Dee,  M Bílek (2003)
              Airway collapse and reopening due to mechanical ventilation exerts mechanical stress on airway walls and injures surfactant-compromised lungs. The reopening of a collapsed airway was modeled experimentally and computationally by the progression of a semi-infinite bubble in a narrow fluid-occluded channel. The extent of injury caused by bubble progression to pulmonary epithelial cells lining the channel was evaluated. Counterintuitively, cell damage increased with decreasing opening velocity. The presence of pulmonary surfactant, Infasurf, completely abated the injury. These results support the hypotheses that mechanical stresses associated with airway reopening injure pulmonary epithelial cells and that pulmonary surfactant protects the epithelium from this injury. Computational simulations identified the magnitudes of components of the stress cycle associated with airway reopening (shear stress, pressure, shear stress gradient, or pressure gradient) that may be injurious to the epithelial cells. By comparing these magnitudes to the observed damage, we conclude that the steep pressure gradient near the bubble front was the most likely cause of the observed cellular damage.

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                19 July 2016
                : 11
                : 1623-1638
                [1 ]Department of Critical Care, Pulmonary Unit and Marianthi Simou Applied Biomedical Research and Training Center, Evangelismos General Hospital, University of Athens Medical School
                [2 ]Department of Pathology, Evangelismos General Hospital
                [3 ]1st Department of Pathology, University of Athens Medical School, Athens, Greece
                Author notes
                Correspondence: Theodoros Vassilakopoulos, 1st Department of Critical Care, Pulmonary Unit, Evangelismos General Hospital, University of Athens Medical School, 45-47 Ispilandou Street, 10676 Athens, Greece, Tel +30 21 3204 1952, Fax +30 21 0724 4941, Email tvassil@
                © 2016 Loverdos et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Respiratory medicine

                lung injury, resistive breathing, inflammation


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