Alveolar fibrinolytic capacity suppressed by injurious mechanical ventilation

Dahlem, Peter; Bos, Albert P.; Haitsma, Jack J.; Schultz, Marcus J.; Meijers, Joost C. M.; Lachmann, Burkhard

doi:10.1007/s00134-005-2588-2

Cited by 39 publications

(34 citation statements)

References 40 publications

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“…33 A previous murine model of lung fibrogenesis caused by injurious mechanical ventilation showed that TGF-b1 induced the production of PAI-1 and administering PAI-1 RNA interference inhibited EMT and the progression of pulmonary fibrogenesis. 8,9,15 TGF-b1 can inhibit collagen degradation by inducing PAI-1 expression and thus inhibiting the activities of plasmin and tPA. 15 We demonstrated that high-V T mechanical ventilation increased lung injury, collagen deposition, fibroblast accumulation, increased expression of mesenchymal markers a-SMA and type I collagen, but decreased epithelial marker ZO-1, and PAI-1 and TGF-b1 production.…”

Section: Discussionmentioning

confidence: 99%

Mechanical ventilation augments bleomycin-induced epithelial–mesenchymal transition through the Src pathway

Liu

Kao

et al. 2014

Laboratory Investigation

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Mechanical ventilation used in patients with acute respiratory distress syndrome (ARDS) can damage pulmonary epithelial cells by producing inflammatory cytokines and depositing excess collagen. Src participates in plasminogen activator inhibitor-1 (PAI-1) and transforming growth factor-b1(TGF-b1) production during the fibroproliferative phase of ARDS, which involves a process of epithelial-mesenchymal transition (EMT). The mechanisms regulating interactions between mechanical ventilation and EMT are unclear. We hypothesized that EMT induced by high-tidal volume (V T ) mechanical stretch-augmented lung inflammation occurs through upregulation of the Src pathway. Five days after administering bleomycin to simulate acute lung injury (ALI), male C57BL/6 mice, either wild-type or Src-deficient, aged 3 months, weighing between 25 and 30 g, were exposed to low-V T (6 ml/kg) or high-V T (30 ml/kg) mechanical ventilation with room air for 1-5 h. Nonventilated mice were used as control subjects. We observed that high-V T mechanical ventilation increased microvascular permeability, PAI-1 and TGF-b1 protein levels, Masson's trichrome staining, extracellular collagen levels, collagen gene expression, fibroblast accumulation, positive staining of a-smooth muscle actin and type I collagen, activation of Src signaling and epithelial apoptotic cell death in wild-type mice (Po0.05). Decreased staining of the epithelial marker, Zonula occludents-1, was also observed. Mechanical stretch-augmented EMT and epithelial apoptosis were attenuated in Src-deficient mice and pharmacological inhibition of Src activity by PP2 (Po0.05). Our data suggest that high-V T mechanical ventilation-augmented EMT after bleomycin-induced ALI partially depends on the Src pathway. Acute respiratory distress syndrome (ARDS) is a disorder of acute respiratory failure and manifests as non-cardiogenic pulmonary edema, respiratory distress and hypoxemia. 1,2 Mechanical ventilation with high-tidal volume (V T ) causes severe lung injury (ventilator-induced lung injury (VILI)) characterized by an initial inhomogeneous inflammatory reaction or epithelial injury that is followed by a fibroproliferative phase with fibroblast proliferation. 3-8 Epithelialmesenchymal transition (EMT) is the differentiation of epithelial cells into myofibroblast-like cells, which contributes to the fibroproliferative phase. 3-8 Upregulating Src, the plasminogen activator inhibitor-1 (PAI-1), and the transforming growth factor-b1(TGF-b1) has recently been demonstrated to regulate EMT. 9-14 However, the mechanisms regulating the interactions between mechanical ventilation and EMT remain unclear.PAI-1, a member of the serine protease inhibitor (serpin) gene family, rapidly inhibits both the urokinase-type plasminogen activator and the tissue-type plasminogen activator (tPA). 15 Mice with homozygous deletion of PAI-1 were relatively protected from bleomycin-induced pulmonary fibrogenesis, whereas overexpression of PAI-1 enhanced pulmonary fibrogenesis. 9 As a primary profibrogenic cytokine...

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Section: Discussionmentioning

confidence: 99%

Mechanical ventilation augments bleomycin-induced epithelial–mesenchymal transition through the Src pathway

Liu

Kao

et al. 2014

Laboratory Investigation

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“…Recently, it was demonstrated that in models of VILI, local pulmonary fibrinolysis is suppressed during injurious mechanical ventilation known as ventilator-associated coagulopathy [12,13]. However, the models used were iatrogenic in nature, either a single exposure to lipopolysaccharide [13] or fibrin deposits caused by human plasma without inflammation [12].…”

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confidence: 99%

“…However, the models used were iatrogenic in nature, either a single exposure to lipopolysaccharide [13] or fibrin deposits caused by human plasma without inflammation [12]. Furthermore, in neither of these models was systemic analysis performed.…”

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confidence: 99%

Ventilator-induced coagulopathy in experimental Streptococcus pneumoniae pneumonia

Haitsma

Schultz²,

Hofstra³

et al. 2008

European Respiratory Journal

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Pneumonia, the main cause of acute lung injury, is characterised by a local proinflammatory response and coagulopathy. Mechanical ventilation (MV) is often required. However, MV can lead to additional injury: so-called ventilator-induced lung injury (VILI). Therefore, the current authors investigated the effect of VILI on alveolar fibrin turnover in Streptococcus pneumoniae pneumonia.Pneumonia was induced in rats, followed 48 h later by either lung-protective MV (lower tidal volumes (LVT) and positive end-expiratory pressure (PEEP)) or MV causing VILI (high tidal volumes (HVT) and zero end-expiratory pressure (ZEEP)) for 3 h. Nonventilated pneumonia rats and healthy rats served as controls. Thrombin-antithrombin complexes (TATc), as a measure for coagulation, and plasminogen activator activity, as a measure of fibrinolysis, were determined in bronchoalveolar lavage fluid (BALF) and serum.Pneumonia was characterised by local (BALF) activation of coagulation, resulting in elevated TATc levels and attenuation of fibrinolysis compared with healthy controls. LVT-PEEP did not influence alveolar coagulation or fibrinolysis. HVT-ZEEP did intensify the local procoagulant response: TATc levels rose significantly and levels of the main inhibitor of fibrinolysis, plasminogen activator inhibitor-1, increased significantly. HVT-ZEEP also resulted in systemic elevation of TATc compared with LVT-PEEP.Mechanical ventilation causing ventilator-induced lung injury increases pulmonary coagulopathy in an animal model of Streptococcus pneumoniae pneumonia and results in systemic coagulopathy.

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“…Studies of animal models of VILI showed that high tidal volume ventilation increases alveolar fibrin deposition and systemic PAI-1 activity while lungprotective mechanical ventilation decreases BALF levels of PAI-1, attenuates coagulation, and enhances fibrinolysis [14,21] . Although aerosol administration offers the theoretical advantage of the lungs receiving high concentrations of tPA, we chose intravenous administration because intra-alveolar and intravascular fibrin deposition and high systemic PAI-1 levels are frequently found in the setting of acute lung injury or VILI [5,15] . Intraperitoneal tPA lavage could also reduce intraabdominal PAI-1 concentrations in experimental peritonitis [20] .…”

Section: Discussionmentioning

confidence: 99%

“…Pulmonary fibrin turnover, the deposition of fibrin in the alveolar space, and increased procoagulant activity of bronchoalveolar lavage fluid (BALF) are the pathognomonic features of VILI [5,6] . Alveolar fibrin deposition may lead to surfactant dysfunction, poor gas exchange, decreased lung compliance, and increased ventilatory dependence [7] .…”

Section: Introductionmentioning

confidence: 99%

Tissue plasminogen activator attenuates ventilator-induced lung injury in rats

Huang¹,

Chou²,

Wang³

et al. 2012

Acta Pharmacol Sin

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Aim: To test the hypothesis that the tissue plasminogen activator (tPA) may counteract the inhibitory effect of plasminogen activator inhibitors (PAI) and attenuate lung injury in a rat model of ventilator-induced lung injury (VILI). Methods: Adult male Sprague-Dawley rats were ventilated with a HVZP (high-volume zero PeeP) protocol for 2 h at a tidal volume of 30 mL/kg, a respiratory rate of 25 breaths/min, and an inspired oxygen fraction of 21%. The rats were divided into 3 groups (n=7 for each): HVZP+tPA group receiving tPA (1.25 mg/kg, iv) 15 min before ventilation, HVZP group receiving HVZP+vehicle injection, and a control group receiving no ventilation. After 2 h of ventilation, the rats were killed; blood and lungs were collected for biochemical and histological analyses. Results: HVZP ventilation significantly increased total protein content and the concentration of macrophage inflammatory protein-2 (MIP-2) in the bronchoalveolar lavage fluid (BALF) as well as the lung injury score. Rats that received HVZP ventilation had significantly higher lung PAI-1 mRNA expression, plasma PAI-1 and plasma D-dimer levels than the control animals. tPA treatment significantly reduced the BALF total protein and the lung injury score as compared to the HVZP group. tPA treatment also significantly decreased the plasma D-dimer levels and the HVZP ventilation-induced lung vascular fibrin thrombi. tPA treatment showed no effect on MIP-2 level in BALF.Conclusion: These results demonstrate that VILI increases lung PAI-1 mRNA expression, plasma levels of PAI-1 and D-dimers, lung injury score and vascular fibrin deposition. tPA can attenuate VILI by decreasing capillary-alveolar protein leakage as well as local and systemic coagulation as shown by decreased lung vascular fibrin deposition and plasma D-dimers.

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Alveolar fibrinolytic capacity suppressed by injurious mechanical ventilation

Abstract: Alveolar fibrinolytic capacity is suppressed during mechanical ventilation with high pressure amplitudes due to local production of PAI-1.

Cited by 39 publications

References 40 publications

Mechanical ventilation augments bleomycin-induced epithelial–mesenchymal transition through the Src pathway

Mechanical ventilation augments bleomycin-induced epithelial–mesenchymal transition through the Src pathway

Ventilator-induced coagulopathy in experimental Streptococcus pneumoniae pneumonia

Tissue plasminogen activator attenuates ventilator-induced lung injury in rats

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