Cytosolic phospholipase A2and arachidonic acid metabolites modulate ventilator-induced permeability increases in isolated mouse lungs (original) (raw)
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Journal of Applied Physiology, 2005
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 cPLA2activity, we compared lung injury with and without a PLA2inhibitor 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 cPLA2in 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 wit...
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2007
To determine the role of phosphoinositide 3-OH kinase (PI3K) pathways in the acute vascular permeability increase associated with ventilator-induced lung injury, we ventilated isolated perfused lungs and intact C57BL/6 mice with low and high peak inflation pressures (PIP). In isolated lungs, filtration coefficients ( Kf) increased significantly after ventilation at 30 cmH2O (high PIP) for successive periods of 15, 30 (4.1-fold), and 50 (5.4-fold) min. Pretreatment with 50 μM of the PI3K inhibitor, LY-294002, or 20 μM PP2, a Src kinase inhibitor, significantly attenuated the increase in Kf, whereas 10 μM Akt inhibitor IV significantly augmented the increased Kf. There were no significant differences in Kfor lung wet-to-dry weight (W/D) ratios between groups ventilated with 9 cmH2O PIP (low PIP), with or without inhibitor treatment. Total lung β-catenin was unchanged in any low PIP isolated lung group, but Akt inhibition during high PIP ventilation significantly decreased total β-cate...
Journal of Applied Physiology, 2004
To determine the influence of experimental model and strain differences on the relationship of vascular permeability to inflammatory cytokine production after high peak inflation pressure (PIP) ventilation, we used isolated perfused mouse lung and intact mouse preparations of Balb/c and B6/129 mice ventilated at high and low PIP. Filtration coefficients in isolated lungs and bronchoalveolar lavage (BAL) albumin in intact mice increased within 20–30 min after initiation of high PIP in isolated Balb/c lungs and intact Balb/c, B6/129 wild-type, and p55 and p75 tumor necrosis factor (TNF) dual-receptor null mice. In contrast, the cytokine response was delayed and variable compared with the permeability response. In isolated Balb/c lungs ventilated with 25–27 cmH2O PIP, TNF-α, interleukin (IL)-1β, IL-1α, macrophage inflammatory protein (MIP)-2, and IL-6 concentrations in perfusate were markedly increased in perfusate at 2 and 4 h, but only MIP-2 was detectable in intact Balb/c mice using...
AJP: Lung Cellular and Molecular Physiology, 2007
We have previously implicated calcium entry through stretch-activated cation channels in initiating the acute pulmonary vascular permeability increase in response to high peak inflation pressure (PIP) ventilation. However, the molecular identity of the channel is not known. We hypothesized that the transient receptor potential vanilloid-4 (TRPV4) channel may initiate this acute permeability increase because endothelial calcium entry through TRPV4 channels occurs in response to hypotonic mechanical stress, heat, and P-450 epoxygenase metabolites of arachidonic acid. Therefore, permeability was assessed by measuring the filtration coefficient (Kf) in isolated perfused lungs of C57BL/6 mice after 30-min ventilation periods of 9, 25, and 35 cmH2O PIP at both 35°C and 40°C. Ventilation with 35 cmH2O PIP increased Kf by 2.2-fold at 35°C and 3.3-fold at 40°C compared with baseline, but Kf increased significantly with time at 40°C with 9 cmH2O PIP. Pretreatment with inhibitors of TRPV4 (rut...
Studies on the mechanism of PAF-induced vasopermeability in rat lungs
Prostaglandins, leukotrienes, and essential fatty acids, 1995
The present study evaluated the effect of platelet activating factor (PAF) instilled into rat airways on vascular permeability assessed in isolated lung tissues by Evans blue (EB)-labelled plasma protein extravasation. It was found that intratracheal instillation of PAF induces a dose-dependent increase of EB extravasation in the bronchi (upper and inner) but not in the lung parenchyma. The contribution of eicosanoids to PAF-induced increase of vascular permeability was investigated by treating the animals with selected inhibitors prior to PAF administration. Mepacrine (5 mg/kg), L-663,536 (10 mg/kg), indomethacin (4 mg/kg) and dazoxiben (10 mg/kg) significantly reduced EB extravasation in the bronchi. The PAF antagonists BN-52021 (5 mg/kg), WEB-2086 (1 mg/kg), WEB-2170 (5 mg/kg) and PCA-4248 (3 mg/kg) were all effective in reducing the extravasation. These results suggest that PAF-induced increase of vascular permeability in rat bronchi is mediated by cyclooxygenase and lipoxygenas...
Phosphoinositide 3-OH Kinase Inhibition Prevents Ventilation-induced Lung Cell Activation
American Journal of Respiratory and Critical Care Medicine, 2004
In ARDS patients, protective ventilation strategies reduce mortality and proinflammatory mediator levels. It has been suggested that some of the side effects of mechanical ventilation are caused by the excessive release of mediators capable of causing pulmonary inflammation and tissue destruction (biotrauma). Selective inhibition of this process might be used to minimize the side effects of artificial mechanical ventilation. The present study was designed to identify the cell types and specific signaling mechanisms that are activated by ventilation with increased pressure/volume (overventilation). In isolated perfused mouse lungs, overventilation caused nuclear translocation of NF-κB and enhanced expression of IL-6 mRNA in alveolar macrophages (AM) and alveolar epithelial type II (ATII) cells. The phosphoinositide 3-OH kinase (PI3K) inhibitor Ly294002 prevented nuclear translocation of NF-κB and the subsequent release of IL-6 and MIP-2α in overventilated, but not in endotoxic lungs. Similar results were obtained in rats in vivo, where Ly294002 prevented NF-κB activation by overventilation but not by endotoxin. These findings show that AM and ATII cells contribute to the ventilation-induced release of pro-inflammatory mediators and that selective inhibition of this process is possible without inhibiting the activation of NF-κB by endotoxin.
Frontiers in physiology, 2017
Mechanical ventilation is vital to the management of acute respiratory distress syndrome, but it frequently leads to ventilator-induced lung injury (VILI). Understanding the pathophysiological processes involved in the development of VILI is an essential prerequisite for improving lung-protective ventilation strategies. The goal of this study was to relate the amount and nature of material accumulated in the airspaces to biomarkers of injury and the derecruitment behavior of the lung in VILI. Forty-nine BALB/c mice were mechanically ventilated with combinations of tidal volume and end-expiratory pressures to produce varying degrees of overdistension and atelectasis while lung function was periodically assessed. Total protein, serum protein, and E-Cadherin levels were measured in bronchoalveolar lavage fluid (BALF). Tissue injury was assessed by histological scoring. We found that both high tidal volume and zero positive end-expiratory pressure were necessary to produce significant V...
PLoS ONE, 2013
The accepted protocol to ventilate patients with acute lung injury is to use low tidal volume (V T ) in combination with recruitment maneuvers or positive end-expiratory pressure (PEEP). However, an important aspect of mechanical ventilation has not been considered: the combined effects of PEEP and ventilation modes on the integrity of the epithelium. Additionally, it is implicitly assumed that the best PEEP-V T combination also protects the epithelium. We aimed to investigate the effects of ventilation mode and PEEP on respiratory mechanics, peak airway pressures and gas exchange as well as on lung surfactant and epithelial cell integrity in mice with acute lung injury. HCl-injured mice were ventilated at PEEPs of 3 and 6 cmH 2 O with conventional ventilation (CV), CV with intermittent large breaths (CV LB ) to promote recruitment, and a new mode, variable ventilation, optimized for mice (VV N ). Mechanics and gas exchange were measured during ventilation and surfactant protein (SP)-B, proSP-B and E-cadherin levels were determined from lavage and lung homogenate. PEEP had a significant effect on mechanics, gas exchange and the epithelium. The higher PEEP reduced lung collapse and improved mechanics and gas exchange but it also down regulated surfactant release and production and increased epithelial cell injury. While CV LB was better than CV, VV N outperformed CV LB in recruitment, reduced epithelial injury and, via a dynamic mechanotransduction, it also triggered increased release and production of surfactant. For longterm outcome, selection of optimal PEEP and ventilation mode may be based on balancing lung physiology with epithelial injury. Citation: Thammanomai A, Hamakawa H, Bartolák-Suki E, Suki B (2013) Combined Effects of Ventilation Mode and Positive End-Expiratory Pressure on Mechanics, Gas Exchange and the Epithelium in Mice with Acute Lung Injury. PLoS ONE 8(1): e53934.