YAP Expression in Endothelial Cells Prevents Ventilator-induced Lung Injury

2021 ◽  
Author(s):  
Kai Su ◽  
Jianguo Wang ◽  
Yang Lv ◽  
Ming Tian ◽  
You-Yang Zhao ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Endothelial Cells ◽  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Protein Content ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Vascular Endothelial ◽  
Wild Type ◽  
Ventilator Induced Lung Injury

Ventilator-induced lung injury is associated with an increase in mortality in patients with respiratory dysfunction, although mechanical ventilation is an essential intervention implemented in the intensive care unit. Intrinsic molecular mechanisms for minimizing lung inflammatory injury during mechanical ventilation remain poorly defined. We hypothesize that Yes-associated protein (YAP) expression in endothelial cells protects the lung against ventilator-induced injury. Wild type and endothelial-specific YAP-deficient mice were subjected to a low (7 ml/kg) or high (21 ml/kg) tidal volume (VT) ventilation for 4 h. Infiltration of inflammatory cells into the lung, vascular permeability, lung histopathology, and the levels of inflammatory cytokines were measured. Here we showed that mechanical ventilation with high VT up-regulated YAP protein expression in pulmonary endothelial cells. Endothelial-specific YAP knockout mice following high VT ventilation exhibited increased neutrophil counts and protein content in bronchoalveolar lavage fluid, Evans blue leakage and histological lung injury compared to wild-type littermate controls. Deletion of YAP in endothelial cells exaggerated vascular endothelial (VE)-cadherin phosphorylation, downregulation of vascular endothelial protein tyrosine phosphatase (VE-PTP) and dissociation of VE-cadherin and catenins following mechanical ventilation. Importantly, exogenous expression of wild type VE-PTP in the pulmonary vasculature rescued YAP ablation-induced increases in neutrophil counts and protein content in bronchoalveolar lavage fluid, vascular leakage, and histological lung injury as well as VE-cadherin phosphorylation and dissociation from catenins following ventilation. These data demonstrate that YAP expression in endothelial cells suppresses lung inflammatory response and edema formation by modulating VE-PTP-mediated VE-cadherin phosphorylation and thus plays a protective role in ventilator-induced lung injury.

A Metabolomic Approach to the Pathogenesis of Ventilator-induced Lung Injury

2014 ◽  
Vol 120 (3) ◽  
pp. 694-702 ◽  
Author(s):  
José L. Izquierdo-García ◽  
Shama Naz ◽  
Nicolás Nin ◽  
Yeny Rojas ◽  
Marcela Erazo ◽  
...  
Keyword(s):  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Tidal Volume ◽  
Lung Tissue ◽  
Metabolic Profiling ◽  
Metabolic Profile ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Positive End Expiratory Pressure ◽  
Ventilator Induced Lung Injury

Abstract Background: Global metabolic profiling using quantitative nuclear magnetic resonance spectroscopy (MRS) and mass spectrometry (MS) is useful for biomarker discovery. The objective of this study was to discover biomarkers of acute lung injury induced by mechanical ventilation (ventilator-induced lung injury [VILI]), by using MRS and MS. Methods: Male Sprague–Dawley rats were subjected to two ventilatory strategies for 2.5 h: tidal volume 9 ml/kg, positive end-expiratory pressure 5 cm H2O (control, n = 14); and tidal volume 25 ml/kg and positive end-expiratory pressure 0 cm H2O (VILI, n = 10). Lung tissue, bronchoalveolar lavage fluid, and serum spectra were obtained by high-resolution magic angle spinning and 1H-MRS. Serum spectra were acquired by high-performance liquid chromatography coupled to quadupole-time of flight MS. Principal component and partial least squares analyses were performed. Results: Metabolic profiling discriminated characteristics between control and VILI animals. As compared with the controls, animals with VILI showed by MRS higher concentrations of lactate and lower concentration of glucose and glycine in lung tissue, accompanied by increased levels of glucose, lactate, acetate, 3-hydroxybutyrate, and creatine in bronchoalveolar lavage fluid. In serum, increased levels of phosphatidylcholine, oleamide, sphinganine, hexadecenal and lysine, and decreased levels of lyso-phosphatidylcholine and sphingosine were identified by MS. Conclusions: This pilot study suggests that VILI is characterized by a particular metabolic profile that can be identified by MRS and MS. The metabolic profile, though preliminary and pending confirmation in larger data sets, suggests alterations in energy and membrane lipids. SUPPLEMENTAL DIGITAL CONTENT IS AVAILABLE IN THE TEXT

scholarly journals Mild hypothermia attenuates changes in respiratory system mechanics and modifies cytokine concentration in bronchoalveolar lavage fluid during low lung volume ventilation

2010 ◽  
pp. 937-944
Author(s):  
P Dostál ◽  
M Šenkeřík ◽  
R Pařízková ◽  
D Bareš ◽  
P Živný ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Respiratory System ◽  
Bronchoalveolar Lavage Fluid ◽  
Mild Hypothermia ◽  
Lavage Fluid ◽  
Cytokine Concentration ◽  
Volume Ventilation ◽  
Hypothermia Group

Hypothermia was shown to attenuate ventilator-induced lung injury due to large tidal volumes. It is unclear if the protective effect of hypothermia is maintained under less injurious mechanical ventilation in animals without previous lung injury. Tracheostomized rats were randomly allocated to non-ventilated group (group C) or ventilated groups of normothermia (group N) and mild hypothermia (group H). After two hours of mechanical ventilation with inspiratory fraction of oxygen 1.0, respiratory rate 60 min-1, tidal volume 10 ml·kg-1, positive end-expiratory pressure (PEEP) 2 cm H2O or immediately after tracheostomy in non-ventilated animals inspiratory pressures were recorded, rats were sacrificed, pressure-volume (PV) curve of respiratory system constructed, bronchoalveolar lavage (BAL) fluid and aortic blood samples obtained. Group N animals exhibited a higher rise in peak inspiratory pressures in comparison to group H animals. Shift of the PV curve to right, higher total protein and interleukin6 levels in BAL fluid were observed in normothermia animals in comparison with hypothermia animals and non-ventilated controls. Tumor necrosis factor-α was lower in the hypothermia group in comparison with normothermia and non-ventilated groups. Mild hypothermia attenuated changes in respiratory system mechanics and modified cytokine concentration in bronchoalveolar lavage fluid during low lung volume ventilation in animals without previous lung injury.

scholarly journals Cyclooxygenase-2 Activity Regulates Recruitment of VEGF-Secreting Ly6Chigh Monocytes in Ventilator-Induced Lung Injury

2019 ◽  
Vol 20 (7) ◽  
pp. 1771
Author(s):  
Tzu-Hsiung Huang ◽  
Pin-Hui Fang ◽  
Jhy-Ming Li ◽  
Huan-Yuan Ling ◽  
Chieh-Mo Lin ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Cyclooxygenase 2 ◽  
Leukocyte Infiltration ◽  
Pulmonary Vascular Permeability ◽  
Ventilator Induced Lung Injury ◽  
Cox 2

Mechanical ventilation is usually required for saving lives in critically ill patients; however, it can cause ventilator-induced lung injury (VILI). As VEGF-secreting Ly6Chigh monocytes are involved in VILI pathogenesis, we investigated whether cyclooxygenase-2 (COX-2) activity regulates the recruitment of VEGF-secreting Ly6Chigh monocytes during VILI. The clinically relevant two-hit mouse model of VILI, which involves the intravenous injection of lipopolysaccharide prior to high tidal volume (HTV)-mechanical ventilation, was used in this study. To investigate the role of COX-2 in the recruitment of VEGF-secreting Ly6Chigh monocytes during VILI, celecoxib, which is a clinical COX-2 inhibitor, was administered 1 h prior to HTV-mechanical ventilation. Pulmonary vascular permeability and leakage, inflammatory leukocyte infiltration, and lung oxygenation levels were measured to assess the severity of VILI. HTV-mechanical ventilation significantly increased the recruitment of COX-2-expressing Ly6Chigh, but not Ly6Clow, monocytes. Celecoxib significantly diminished the recruitment of Ly6Chigh monocytes, attenuated the levels of VEGF and total protein in bronchoalveolar lavage fluid, and restored pulmonary oxygenation during VILI. Our findings demonstrate that COX-2 activity is important in the recruitment of VEGF-secreting Ly6Chigh monocytes, which are involved in VILI pathogenesis, and indicate that the suppression of COX-2 activity might be a useful strategy in mitigating VILI.

scholarly journals Mechanical Ventilation with Lower Tidal Volumes and Positive End-expiratory Pressure Prevents Pulmonary Inflammation in Patients without Preexisting Lung Injury

2008 ◽  
Vol 108 (1) ◽  
pp. 46-54 ◽  
Author(s):  
Esther K. Wolthuis ◽  
Goda Choi ◽  
Mark C. Dessing ◽  
Paul Bresser ◽  
Rene Lutter ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Bronchoalveolar Lavage Fluid ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Lavage Fluid ◽  
Positive End Expiratory Pressure ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein

Background Mechanical ventilation with high tidal volumes aggravates lung injury in patients with acute lung injury or acute respiratory distress syndrome. The authors sought to determine the effects of short-term mechanical ventilation on local inflammatory responses in patients without preexisting lung injury. Methods Patients scheduled to undergo an elective surgical procedure (lasting > or = 5 h) were randomly assigned to mechanical ventilation with either higher tidal volumes of 12 ml/kg ideal body weight and no positive end-expiratory pressure (PEEP) or lower tidal volumes of 6 ml/kg and 10 cm H2O PEEP. After induction of anesthesia and 5 h thereafter, bronchoalveolar lavage fluid and/or blood was investigated for polymorphonuclear cell influx, changes in levels of inflammatory markers, and nucleosomes. Results Mechanical ventilation with lower tidal volumes and PEEP (n = 21) attenuated the increase of pulmonary levels of interleukin (IL)-8, myeloperoxidase, and elastase as seen with higher tidal volumes and no PEEP (n = 19). Only for myeloperoxidase, a difference was found between the two ventilation strategies after 5 h of mechanical ventilation (P < 0.01). Levels of tumor necrosis factor alpha, IL-1alpha, IL-1beta, IL-6, macrophage inflammatory protein 1alpha, and macrophage inflammatory protein 1beta in the bronchoalveolar lavage fluid were not affected by mechanical ventilation. Plasma levels of IL-6 and IL-8 increased with mechanical ventilation, but there were no differences between the two ventilation groups. Conclusion The use of lower tidal volumes and PEEP may limit pulmonary inflammation in mechanically ventilated patients without preexisting lung injury. The specific contribution of both lower tidal volumes and PEEP on the protective effects of the lung should be further investigated.

scholarly journals Protective Effect of Oxytocin on Ventilator-Induced Lung Injury Through NLRP3-Mediated Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaomei Yang ◽  
Xiaona An ◽  
Cheng Wang ◽  
Feng Gao ◽  
Yicheng Lin ◽  
...  
Keyword(s):  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Protective Effect ◽  
Bronchoalveolar Lavage Fluid ◽  
Life Support ◽  
Inflammatory Responses ◽  
Weight Ratio ◽  
Lavage Fluid ◽  
Caspase 1 ◽  
Ventilator Induced Lung Injury

Mechanical ventilation is an indispensable life-support treatment for acute respiratory failure in critically ill patients, which is generally believed to involve uncontrolled inflammatory responses. Oxytocin (OT) has been reported to be effective in animal models of acute lung injury. However, it is not clear whether Oxytocin has a protective effect on ventilator-induced lung injury (VILI). Therefore, in this study, we aimed to determine whether OT can attenuate VILI and explore the possible mechanism of this protection. To this end, a mouse VILI model was employed. Mice were pretreated with OT 30 min before the intraperitoneal injection of saline or nigericin and ventilation for 4 h, after which they were euthanized. Pathological changes, lung wet/dry (W/D) weight ratio, myeloperoxidase (MPO) activity, the levels of inflammatory cytokines [i.e., interleukin (IL)-1β, IL-6, and IL-18] in lung tissues and bronchoalveolar lavage fluid (BALF), and expression of NLRP3, Toll-like receptor 4 (TLR4), caspase-1, nuclear factor (NF)-κB, and GSDMD in lung tissues were measured. OT treatment could reduce pathological injury, the W/D ratio, and MPO activity in VILI mice. Our data also indicated that OT administration alleviated the expression of TLR4/My-D88 and the activation of NF-κB, NLRP3, and caspase-1 in lung tissues from the VILI mice model. Furthermore, OT also decreased the levels of IL-1β, IL-6, and IL-18 in the bronchoalveolar lavage fluid. Moreover, the OT administration may alleviate the activation of GSDMD partially through its effects on the NLRP3-mediated pathway. Collectively, OT exerted a beneficial effect on VILI by downregulating TLR4-and NLRP3-mediated inflammatory pathways.

scholarly journals Ginsenoside ameliorated ventilator-induced lung injury in rats

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Woo Hyun Cho ◽  
Yun Hak Kim ◽  
Hye Jin Heo ◽  
Dohyung Kim ◽  
Tae Won Kwak ◽  
...  
Keyword(s):  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Bronchoalveolar Lavage Fluid ◽  
Dry Weight ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Lung Injury Score ◽  
Control Group ◽  
Ventilator Induced Lung Injury ◽  
Tnf Α

Abstract Background Ginsenosides have antioxidant and anti-inflammatory features. This study aimed to evaluate the biologic effects of ginsenoside Rb2 pretreatment on ventilator-induced lung injury (VILI) in rats. Methods Rats were divided into four groups with 12 rats per group: control; low tidal volume (TV), TV of 6 mL/kg, VILI, TV of 20 mL/kg, positive end-expiratory pressure of 5 cm H2O, and respiratory rate of 60 breaths per minute for 3 h at an inspiratory oxygen fraction of 0.21; and ginsenosides, treated the same as the VILI group but with 20 mg/kg intraperitoneal ginsenoside pretreatment. Morphology was observed with a microscope to confirm the VILI model. Wet-to-dry weight ratios, protein concentrations, and pro-inflammatory cytokines in the bronchoalveolar lavage fluid were measured. RNA sequencing of the lung tissues was conducted to analyze gene expression. Results High TV histologically induced VILI with alveolar edema and infiltration of inflammatory cells. Ginsenosides pretreatment significantly reduced the histologic lung injury score compared to the VILI group. Wet-to-dry weight ratios, malondialdehyde, and TNF-α in bronchoalveolar lavage fluid were significantly higher in the VILI group and ginsenoside pretreatment mitigated these effects. In the immunohistochemistry assay, ginsenoside pretreatment attenuated the TNF-α upregulation induced by VILI. We identified 823 genes differentially presented in the VILI group compared to the control group. Of the 823 genes, only 13 genes (Arrdc2, Cygb, Exnef, Lcn2, Mroh7, Nsf, Rexo2, Srp9, Tead3, Ephb6, Mvd, Sytl4, and Ube2l6) recovered to control levels in the ginsenoside group. Conclusions Ginsenosides inhibited the inflammatory and oxidative stress response in VILI. Further studies are required on the 13 genes, including LCN2.

Mechanical Ventilation Induces Neutrophil Extracellular Trap Formation

2015 ◽  
Vol 122 (4) ◽  
pp. 864-875 ◽  
Author(s):  
Christopher Yildiz ◽  
Nades Palaniyar ◽  
Gail Otulakowski ◽  
Meraj A. Khan ◽  
Martin Post ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Bronchoalveolar Lavage Fluid ◽  
High Mobility ◽  
Lavage Fluid ◽  
High Mobility Group ◽  
Interleukin 1Β ◽  
Histone 3 ◽  
Dnase Treatment

Abstract Background: Mechanical ventilation can injure the lung and induce a proinflammatory state; such ventilator-induced lung injury (VILI) is associated with neutrophil influx. Neutrophils release DNA and granular proteins as cytotoxic neutrophil extracellular traps (NETs). The authors hypothesized that NETs were produced in a VILI model and may contribute to injury. Methods: In a two-hit lipopolysaccharide/VILI mouse model with and without intratracheal deoxyribonuclease (DNase) treatment or blockade of known inducers of NET formation (NETosis), the authors assessed compliance, bronchoalveolar lavage fluid protein, markers of NETs (citrullinated histone-3 and DNA), and markers of inflammation. Results: Although lipopolysaccharide recruited neutrophils to airways, the addition of high tidal mechanical ventilation was required for significant induction of NETs markers (e.g., bronchoalveolar lavage fluid DNA: 0.4 ± 0.07 µg/ml [mean ± SEM], P < 0.05 vs. all others, n = 10 per group). High tidal volume mechanical ventilation increased airway high-mobility group box 1 protein (0.91 ± 0.138 vs. 0.60 ± 0.095) and interleukin-1β in lipopolysaccharide-treated mice (22.4 ± 0.87 vs. 17.0 ± 0.50 pg/ml, P < 0.001) and tended to increase monocyte chemoattractant protein-1 and interleukin-6. Intratracheal DNase treatment reduced NET markers (bronchoalveolar lavage fluid DNA: 0.23 ± 0.038 vs. 0.88 ± 0.135 µg/ml, P < 0.001; citrullinated histone-3: 443 ± 170 vs. 1,824 ± 403, P < 0.01, n = 8 to 10) and attenuated the loss of static compliance (0.9 ± 0.14 vs. 1.58 ± 0.17 ml/mmHg, P < 0.01, n = 19 to 20) without significantly impacting other measures of injury. Blockade of high-mobility group box 1 (with glycyrrhizin) or interleukin-1β (with anakinra) did not prevent NETosis or protect against injury. Conclusions: NETosis was induced in VILI, and DNase treatment eliminated NETs. In contrast to experimental transfusion-related acute lung injury, NETs do not play a major pathogenic role in the current model of VILI.

scholarly journals Lung injury induced by short-term mechanical ventilation with hyperoxia and its mitigation by deferoxamine in rats

2020 ◽  
Author(s):  
Xiao-Xia Wang ◽  
Xiao-Lan Sha ◽  
Yulan Li ◽  
Chun-Lan Li ◽  
Su-Heng Chen ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Bronchoalveolar Lavage Fluid ◽  
Weight Ratio ◽  
Lavage Fluid ◽  
Tissue Homogenate ◽  
Short Term ◽  
Short Period ◽  
The Right

Abstract Backgroud Long-term mechanical ventilation with hyperoxia can induce lung injury.General anesthesia is associated with a very high incidence of hyperoxaemia, despite it usually lasts for a very short period of time. It still remains unclear whether short-term mechanical ventilation with hyperoxia has an adverse impact or cause injury to the lungs. The present study aimed to assess whether short-term mechanical ventilation with hyperoxia causes lung injury in rats and whether deferoxamine(DFO)could mitigate such injury to the lungs and explore the possible mechanism. Methods Twenty-four SD rats were randomly divided into 3 groups:mechanical ventilated with normoxia group (MV group, FiO2 =21%), with hyperoxia group(HMV group, FiO2 =90%), or with hyperoxia+DFO group(HMV+DFO group, FiO2 =90%). Mechanical ventilation under different oxygen concentrations was given for 4h. The HMV+DFO group received continuous intravenous infusion of DFO at 200mg•kg -1 •d -1 , while the MV and HMV groups received an equal volume of NS. Carotid artery intubation was carried out to monitor the blood gas parameters under mechanical ventilation for 2h and 4h, respectively, and the oxygenation index(OI) was calculated. After 4h ventilation, the right anterior lobe of the lung and bronchoalveolar lavage fluid from the right lung was sampled for pathological and biochemical assays. Results PaO2 in the HMV and HMV+DFO groups were significantly higher, but the OI were significantly lower than those of the MV group( p <0.01), while PaO2 and OI between HMV+DFO and HMV groups did not differ significantly. The lung pathological scores and the wet-to-dry weight ratio(W/D) in the HMV and HMV+DFO groups were significantly higher than those of the MV group, but score and the W/D were reduced by DFO( p <0.05,HMV+DFOvs.HMV). Biochemically, HMV resulted in significant reductions in SP-C, SP-D, and GR levels and elevation of XOD in both the Bronchoalveolar lavage fluid and the lung tissue homogenate, and all these changes were prevented or significantly reverted by DFO. Conclusions Mechanical ventilation with hyperoxia for 4h induced oxidative injury of the lungs, accompanied by a dramatic reduction in the concentrations of SP-C and SP-D. DFO could mitigate such injury by lowering XOD activity and elevating GR activity.

scholarly journals Treatment with senicapoc in a porcine model of acute respiratory distress syndrome

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Asbjørn G. Petersen ◽  
Peter C. Lind ◽  
Anne-Sophie B. Jensen ◽  
Mark A. Eggertsen ◽  
Asger Granfeldt ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Lung Injury ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Bronchoalveolar Lavage ◽  
Primary Endpoint ◽  
Bronchoalveolar Lavage Fluid ◽  
Distress Syndrome ◽  
Pulmonary Hemorrhage ◽  
Lavage Fluid

Abstract Background Senicapoc is a potent and selective blocker of KCa3.1, a calcium-activated potassium channel of intermediate conductance. In the present study, we investigated whether there is a beneficial effect of senicapoc in a large animal model of acute respiratory distress syndrome (ARDS). The primary end point was the PaO2/FiO2 ratio. Methods ARDS was induced in female pigs (42–49 kg) by repeated lung lavages followed by injurious mechanical ventilation. Animals were then randomly assigned to vehicle (n = 9) or intravenous senicapoc (10 mg, n = 9) and received lung-protective ventilation for 6 h. Results Final senicapoc plasma concentrations were 67 ± 18 nM (n = 9). Senicapoc failed to change the primary endpoint PaO2/FiO2 ratio (senicapoc, 133 ± 23 mmHg; vehicle, 149 ± 68 mmHg). Lung compliance remained similar in the two groups. Senicapoc reduced the level of white blood cells and neutrophils, while the proinflammatory cytokines TNFα, IL-1β, and IL-6 in the bronchoalveolar lavage fluid were unaltered 6 h after induction of the lung injury. Senicapoc-treatment reduced the level of neutrophils in the alveolar space but with no difference between groups in the cumulative lung injury score. Histological analysis of pulmonary hemorrhage indicated a positive effect of senicapoc on alveolar–capillary barrier function, but this was not supported by measurements of albumin content and total protein in the bronchoalveolar lavage fluid. Conclusions In summary, senicapoc failed to improve the primary endpoint PaO2/FiO2 ratio, but reduced pulmonary hemorrhage and the influx of neutrophils into the lung. These findings open the perspective that blocking KCa3.1 channels is a potential treatment to reduce alveolar neutrophil accumulation and improve long-term outcome in ARDS.

scholarly journals A role for bronchial epithelial autotaxin in ventilator-induced lung injury

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Ioanna Nikitopoulou ◽  
Ioanna Ninou ◽  
Nikolaos Manitsopoulos ◽  
Ioanna Dimopoulou ◽  
Stylianos E. Orfanos ◽  
...  
Keyword(s):  
Lung Injury ◽  
Protein Concentration ◽  
Bronchoalveolar Lavage Fluid ◽  
Pulmonary Inflammation ◽  
Small Animal ◽  
Lavage Fluid ◽  
Bronchial Epithelial ◽  
Ventilator Induced Lung Injury ◽  
Lung Histopathology ◽  
Genetic Deletion

Abstract Background The pathophysiology of acute respiratory distress syndrome (ARDS) may eventually result in heterogeneous lung collapse and edema-flooded airways, predisposing the lung to progressive tissue damage known as ventilator-induced lung injury (VILI). Autotaxin (ATX; ENPP2), the enzyme largely responsible for extracellular lysophosphatidic acid (LPA) production, has been suggested to play a pathogenic role in, among others, pulmonary inflammation and fibrosis. Methods C57BL/6 mice were subjected to low and high tidal volume mechanical ventilation using a small animal ventilator: respiratory mechanics were evaluated, and plasma and bronchoalveolar lavage fluid (BALF) samples were obtained. Total protein concentration was determined, and lung histopathology was further performed Results Injurious ventilation resulted in increased BALF levels of ATX. Genetic deletion of ATX from bronchial epithelial cells attenuated VILI-induced pulmonary edema. Conclusion ATX participates in VILI pathogenesis.

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