Exposure to mechanical ventilation promotes tolerance to ventilator-induced lung injury by Ccl3 downregulation

2015 ◽  
Vol 309 (8) ◽  
pp. L847-L856 ◽  
Author(s):  
Jorge Blázquez-Prieto ◽  
Inés López-Alonso ◽  
Laura Amado-Rodríguez ◽  
Estefanía Batalla-Solís ◽  
Adrián González-López ◽  
...  
Keyword(s):  
High Pressure ◽  
Lung Injury ◽  
Molecular Mechanisms ◽  
Peak Pressure ◽  
Lung Damage ◽  
Previous Exposure ◽  
Neutrophilic Infiltration ◽  
Ventilator Induced Lung Injury ◽  
Inflammatory Protein ◽  
Albumin Content

Inflammation plays a key role in the development of ventilator-induced lung injury (VILI). Preconditioning with a previous exposure can damp the subsequent inflammatory response. Our objectives were to demonstrate that tolerance to VILI can be induced by previous low-pressure ventilation, and to identify the molecular mechanisms responsible for this phenomenon. Intact 8- to 12-wk-old male CD1 mice were preconditioned with 90 min of noninjurious ventilation [peak pressure 17 cmH2O, positive end-expiratory pressure (PEEP) 2 cmH2O] and extubated. Seven days later, preconditioned mice and intact controls were submitted to injurious ventilation (peak pressure 20 cmH2O, PEEP 0 cmH2O) for 2 h to induce VILI. Preconditioned mice showed lower histological lung injury scores, bronchoalveolar lavage albumin content, and lung neutrophilic infiltration after injurious ventilation, with no differences in Il6 or Il10 expression. Microarray analyses revealed a downregulation of Calcb, Hspa1b, and Ccl3, three genes related to tolerance phenomena, in preconditioned animals. Among the previously identified genes, only Ccl3, which encodes the macrophage inflammatory protein 1 alpha (MIP-1α), showed significant differences between intact and preconditioned mice after high-pressure ventilation. In separate, nonconditioned animals, treatment with BX471, a specific blocker of CCR1 (the main receptor for MIP-1α), decreased lung damage and neutrophilic infiltration caused by high-pressure ventilation. We conclude that previous exposure to noninjurious ventilation induces a state of tolerance to VILI. Downregulation of the chemokine gene Ccl3 could be the mechanism responsible for this effect.

TLR4 is required for macrophage efferocytosis during resolution of ventilator-induced lung injury

2021 ◽  
Vol 321 (4) ◽  
pp. L787-L801
Author(s):  
Kai Su ◽  
Lulong Bo ◽  
Chunling Jiang ◽  
Xiaoming Deng ◽  
You-Yang Zhao ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Alveolar Macrophage ◽  
Alveolar Macrophages ◽  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Lung Damage ◽  
Lung Edema ◽  
Apoptotic Cells ◽  
Ventilator Induced Lung Injury

Mechanical ventilation is a life-sustaining therapy for patients with respiratory failure but can cause further lung damage known as ventilator-induced lung injury (VILI). However, the intrinsic molecular mechanisms underlying recovery of VILI remain unknown. Phagocytosis of apoptotic cells (also known as efferocytosis) is a key mechanism orchestrating successful resolution of inflammation. Here we show the positive regulation of macrophage Toll-like receptor (TLR) 4 in efferocytosis and resolution of VILI. Mice were depleted of alveolar macrophages and then subjected to injurious ventilation (tidal volume, 20 mL/kg) for 4 h. On day 1 after mechanical ventilation, Tlr4+/+ or Tlr4−/− bone marrow-derived macrophages (BMDMs) were intratracheally administered to alveolar macrophage-depleted mice. We observed that mice depleted of alveolar macrophages exhibited defective resolution of neutrophilic inflammation, exuded protein, lung edema, and lung tissue injury after ventilation, whereas these delayed responses were reversed by administration of Tlr4+/+ BMDMs. Importantly, these proresolving effects by Tlr4+/+ BMDMs were abolished in mice receiving Tlr4−/− BMDMs. The number of macrophages containing apoptotic cells or bodies in bronchoalveolar lavage fluid was much less in mice receiving Tlr4−/− BMDMs than that in those receiving Tlr4+/+ BMDMs. Macrophage TLR4 deletion facilitated a disintegrin and metalloprotease 17 maturation and enhanced Mer cleavage in response to mechanical ventilation. Heat shock protein 70 dramatically increased Mer tyrosine kinase surface expression, phagocytosis of apoptotic neutrophils, and rescued the inflammatory phenotype in alveolar macrophage-depleted mice receiving Tlr4+/+ BMDMs, but not Tlr4−/− BMDMs. Our results suggest that macrophage TLR4 promotes resolution of VILI via modulation of Mer-mediated efferocytosis.

CYCLIN-DEPENDENT KINASE INHIBITION REDUCES LUNG DAMAGE IN A MOUSE MODEL OF VENTILATOR-INDUCED LUNG INJURY

Shock ◽  
2012 ◽  
Vol 38 (4) ◽  
pp. 375-380 ◽  
Author(s):  
Arie J. Hoogendijk ◽  
Maria T. Kuipers ◽  
Tom van der Poll ◽  
Marcus J. Schultz ◽  
Catharina W. Wieland
Keyword(s):  
Lung Injury ◽  
Mouse Model ◽  
Lung Damage ◽  
Cyclin Dependent Kinase ◽  
Kinase Inhibition ◽  
Ventilator Induced Lung Injury

scholarly journals Experimental Ventilator-induced Lung Injury

2009 ◽  
Vol 110 (6) ◽  
pp. 1341-1347 ◽  
Author(s):  
Jesús Villar ◽  
Maria Teresa Herrera-Abreu ◽  
Francisco Valladares ◽  
Mercedes Muros ◽  
Lina Pérez-Méndez ◽  
...  
Keyword(s):  
Lung Injury ◽  
Fatal Outcome ◽  
Experimental Studies ◽  
Lung Damage ◽  
Cytokine Gene Expression ◽  
High Peep ◽  
Necrosis Factor Alpha ◽  
Ventilator Induced Lung Injury ◽  
Airway Pressures

Background Previous experimental studies of ventilator-induced lung injury have shown that positive end-expiratory pressure (PEEP) is protective. The authors hypothesized that the application of PEEP during volume-controlled ventilation with a moderately high tidal volume (VT) in previously healthy in vivo rats does not attenuate ventilator-induced lung injury if the peak airway pressure markedly increases during the application of PEEP. Methods Sixty healthy, male Sprague-Dawley rats were anesthetized and randomized to be mechanically ventilated for 4 h at (1) VT of 6 ml/kg, (2) VT of 20 ml/kg, or (3) VT of 20 ml/kg plus 10 cm H2O of PEEP. Peak airway pressures, gas exchange, histologic evaluation, mortality, total lung tissue cytokine gene expression, and serum cytokine concentrations were analyzed. Results Peak airway pressures exceeded 30 cm H2O with high VT plus PEEP. All lungs ventilated with high VT had perivascular edema and inflammatory infiltrates. In addition, those ventilated with PEEP had small hemorrhages foci. Five animals from the high VT plus PEEP group died (P = 0.020). Animals ventilated with high VT (with or without PEEP) had a substantial increase in serum interleukin-6 (P = 0.0002), and those ventilated with high VT plus PEEP had a 5.5-fold increase in systemic levels of tumor necrosis factor-alpha (P = 0.007). Conclusions In contrast to previous reports, PEEP exacerbated lung damage and contributed to fatal outcome in an in vivo, mild overdistension model of ventilator-induced lung injury in previously healthy rats. That is, the addition of high PEEP to a constant large VT causes injury in previously healthy animals.

scholarly journals NADPH Oxidase 4 Signaling in a Ventilator-induced Lung Injury Mouse Model

2021 ◽  
Author(s):  
Sang Hoon Lee ◽  
Mi Hwa Shin ◽  
Ah Young Leem ◽  
Su Hwan Lee ◽  
Kyung Soo Chung ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lavage Fluid ◽  
Lung Damage ◽  
Control Group ◽  
Group 4 ◽  
Ventilator Induced Lung Injury ◽  
Cell Counts ◽  
Group 5 ◽  
Group 2

Abstract For patients with acute respiratory distress syndrome, a ventilator is essential to supply oxygen to tissues, but it may also cause lung damage. We investigated the role of NOX4 in a ventilator-induced lung injury (VILI) model.Wild-type (WT) male C57BL/6J mice and NOX4 knockout (KO) male mice were divided into five groups: (1) control group; (2) high tidal ventilation (HTV) group: WT mice + HTV; (3) NOX4 KO group; (4) NOX4 KO with HTV group; (5) NOX4 inhibitor group: WT mice + HTV + NOX4 inhibitor. In addition, the relationship between EphA2 (which is related to lung injury) and NOX4 was investigated using EphA2 KO mice, and NOX4 levels in the bronchoalveolar lavage fluid (BALF) of 38 patients with pneumonia were examined.In the NOX4 inhibitor group, cell counts and protein concentrations from BALF were significantly lower than those in the HTV group (both, p<0.001). In the NOX4 KO group and the NOX4 inhibitor group, EphA2 levels were significantly lower than those in the HTV group (p<0.001). NOX4 levels were significantly higher in patients with pneumonia and patients who received ventilator treatment in the ICU.In the VILI model, it may be possible to block VILI using NOX4 antibodies.

Susceptibility to ozone-induced acute lung injury in iNOS-deficient mice

2002 ◽  
Vol 282 (3) ◽  
pp. L540-L545 ◽  
Author(s):  
Nicholas J. Kenyon ◽  
Albert van der Vliet ◽  
Bettina C. Schock ◽  
Tatsuya Okamoto ◽  
Gabrielle M. McGrew ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lung Injury ◽  
Knockout Mice ◽  
Lung Damage ◽  
Ozone Exposure ◽  
Wild Type ◽  
Cell Content ◽  
Inflammatory Protein ◽  
Inos Knockout Mice ◽  
Oxide Synthase

Mice deficient in inducible nitric oxide synthase (iNOS; C57Bl/6Ai-[KO] NOS2 N5) or wild-type C57Bl/6 mice were exposed to 1 part/million of ozone 8 h/night or to filtered air for three consecutive nights. Endpoints measured included lavagable total protein, macrophage inflammatory protein (MIP)-2, matrix metalloproteinase (MMP)-9, cell content, and tyrosine nitration of whole lung proteins. Ozone exposure caused acute edema and an inflammatory response in the lungs of wild-type mice, as indicated by significant increases in lavage protein content, MIP-2 and MMP-9 content, and polymorphonuclear leukocytes. The iNOS knockout mice showed significantly greater levels of lung injury by all of these criteria than did the wild-type mice. We conclude that iNOS knockout mice are more susceptible to acute lung damage induced by exposure to ozone than are wild-type C57Bl/6 mice and that protein nitration is associated with the degree of inflammation and not dependent on iNOS-derived nitric oxide.

scholarly journals Hydrogen Sulfide Prevents Formation of Reactive Oxygen Species through PI3K/Akt Signaling and Limits Ventilator-Induced Lung Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Sashko Georgiev Spassov ◽  
Rosa Donus ◽  
Paul Mikael Ihle ◽  
Helen Engelstaedter ◽  
Alexander Hoetzel ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Hydrogen Sulfide ◽  
Lung Injury ◽  
Inflammatory Responses ◽  
Reactive Oxygen ◽  
Akt Signaling ◽  
Lung Damage ◽  
Oxygen Species ◽  
Ventilator Induced Lung Injury ◽  
Oxidative Processes

The development of ventilator-induced lung injury (VILI) is still a major problem in mechanically ventilated patients. Low dose inhalation of hydrogen sulfide (H2S) during mechanical ventilation has been proven to prevent lung damage by limiting inflammatory responses in rodent models. However, the capacity of H2S to affect oxidative processes in VILI and its underlying molecular signaling pathways remains elusive. In the present study we show that ventilation with moderate tidal volumes of 12 ml/kg for 6 h led to an excessive formation of reactive oxygen species (ROS) in mice lungs which was prevented by supplemental inhalation of 80 parts per million of H2S. In addition, phosphorylation of the signaling protein Akt was induced by H2S. In contrast, inhibition of Akt by LY294002 during ventilation reestablished lung damage, neutrophil influx, and proinflammatory cytokine release despite the presence of H2S. Moreover, the ability of H2S to induce the antioxidant glutathione and to prevent ROS production was reversed in the presence of the Akt inhibitor. Here, we provide the first evidence that H2S-mediated Akt activation is a key step in protection against VILI, suggesting that Akt signaling limits not only inflammatory but also detrimental oxidative processes that promote the development of lung injury.

Mechanisms of early pulmonary neutrophil sequestration in ventilator-induced lung injury in mice

2004 ◽  
Vol 287 (5) ◽  
pp. L902-L910 ◽  
Author(s):  
Sharmila Choudhury ◽  
Michael R. Wilson ◽  
Michael E. Goddard ◽  
Kieran P. O'Dea ◽  
Masao Takata
Keyword(s):  
Lung Injury ◽  
Tidal Volume ◽  
Molecular Mechanisms ◽  
Control Ventilation ◽  
Volume Control ◽  
Neutrophil Sequestration ◽  
Ventilator Induced Lung Injury ◽  
Volume Control Ventilation

Polymorphonuclear leukocytes (PMN) play an important role in ventilator-induced lung injury (VILI), but the mechanisms of pulmonary PMN recruitment, particularly early intravascular PMN sequestration during VILI, have not been elucidated. We investigated the physiological and molecular mechanisms of pulmonary PMN sequestration in an in vivo mouse model of VILI. Anesthetized C57/BL6 mice were ventilated for 1 h with high tidal volume (injurious ventilation), low tidal volume and high positive end-expiratory pressure (protective ventilation), or normal tidal volume (control ventilation). Pulmonary PMN sequestration analyzed by flow cytometry of lung cell suspensions was substantially enhanced in injurious ventilation compared with protective and control ventilation, preceding development of physiological signs of lung injury. Anesthetized, spontaneously breathing mice with continuous positive airway pressure demonstrated that raised alveolar pressure alone does not induce PMN entrapment. In vitro leukocyte deformability assay indicated stiffening of circulating leukocytes in injurious ventilation compared with control ventilation. PMN sequestration in injurious ventilation was markedly inhibited by administration of anti-L-selectin antibody, but not by anti-CD18 antibody. These results suggest that mechanical ventilatory stress initiates pulmonary PMN sequestration early in the course of VILI, and this phenomenon is associated with stretch-induced inflammatory events leading to PMN stiffening and mediated by L-selectin-dependent but CD18-independent mechanisms.

Equal increases in respiratory system elastance reflect similar lung damage in experimental ventilator-induced lung injury

2002 ◽  
Vol 28 (2) ◽  
pp. 196-203 ◽  
Author(s):  
Silvio Sibilla ◽  
Stefano Tredici ◽  
Giuliana Porro ◽  
Manuela Irace ◽  
Massimiliano Guglielmi ◽  
...  
Keyword(s):  
Lung Injury ◽  
Respiratory System ◽  
Lung Damage ◽  
Ventilator Induced Lung Injury

Inflammation and matrix remodeling during repair of ventilator-induced lung injury

2011 ◽  
Vol 301 (4) ◽  
pp. L500-L509 ◽  
Author(s):  
Adrián González-López ◽  
Aurora Astudillo ◽  
Emilio García-Prieto ◽  
María Soledad Fernández-García ◽  
Antonio López-Vázquez ◽  
...  
Keyword(s):  
High Pressure ◽  
Acute Respiratory Distress Syndrome ◽  
Lung Injury ◽  
Respiratory Distress Syndrome ◽  
Distress Syndrome ◽  
Matrix Remodeling ◽  
Epithelial Repair ◽  
Ventilator Induced Lung Injury ◽  
Tnf Α ◽  
Repair Phase

High-pressure ventilation triggers different inflammatory and matrix remodeling responses within the lung. Although some of them may cause injury, the involvement of these mediators in repair is largely unknown. To identify mechanisms of repair after ventilator-induced lung injury (VILI), mice were randomly assigned to baseline conditions (no ventilation), injury [90 min of high-pressure ventilation without positive end-expiratory pressure (PEEP)], repair (injury followed by 4 h of low-pressure ventilation with PEEP), and ventilated controls (low-pressure ventilation with PEEP for 90 and 330 min). Histological injury and lung permeability increased during injury, but were partially reverted in the repair group. This was accompanied by a proinflammatory response, together with increases in TNF-α and IFN-γ, which returned to baseline during repair, and a decrease in IL-10. However, macrophage inflammatory protein-2 (MIP-2) and matrix metalloproteinases (MMP)-2 and -9 increased after injury and persisted in being elevated during repair. Mortality in the repair phase was 50%. Survivors showed increased cell proliferation, lower levels of collagen, and higher levels of MIP-2 and MMP-2. Pan-MMP or specific MMP-2 inhibition (but not MIP-2, TNF-α, or IL-4 inhibition) delayed epithelial repair in an in vitro wound model using murine or human alveolar cells cultured in the presence of bronchoalveolar lavage fluid from mice during the repair phase or from patients with acute respiratory distress syndrome, respectively. Similarly, MMP inhibition with doxycycline impaired lung repair after VILI in vivo. In conclusion, VILI can be reverted by normalizing ventilation pressures. An adequate inflammatory response and extracellular matrix remodeling are essential for recovery. MMP-2 could play a key role in epithelial repair after VILI and acute respiratory distress syndrome.

scholarly journals High Expression of CXCL10/CXCR3 in Ventilator-Induced Lung Injury Caused by High Mechanical Power

2022 ◽  
Vol 2022 ◽  
pp. 1-9
Author(s):  
Yongpeng Xie ◽  
Hui Zheng ◽  
Zhifang Mou ◽  
Yanli Wang ◽  
Xiaomin Li
Keyword(s):  
Mast Cells ◽  
Lung Injury ◽  
Mrna Expression ◽  
Rat Plasma ◽  
Lung Damage ◽  
Mechanical Power ◽  
Ventilator Induced Lung Injury ◽  
Rat Lungs ◽  
Potential Biomarker ◽  
Power Group

Background. The energy delivered by a ventilator to the respiratory system in one minute is defined as mechanical power (MP). However, the effect of ventilator-induced lung injury (VILI) in patients suffering from acute respiratory distress syndrome (ARDS) is still unknown. Our previous studies revealed that CXCL10 may be a potential biomarker of lung injury in ARDS. Therefore, the aim of this study was to compare the lung injury of rats and patients under different MP conditions to explore the involvement of CXCL10 and its receptor CXCR3 in VILI. Methods. Patients were divided into the high mechanical power group (HMPp group) and low mechanical power group (LMPp group), while rats were assigned to the high mechanical power group (HMPr group), medium mechanical power group (MMPr group), and low mechanical power group (LMPr group). CXCL10 and CXCR3 plasma content in ARDS patients and rats under ventilation at different MP was measured, as well as their protein and mRNA expression in rat lungs. Results. CXCL10 and CXCR3 content in the plasma of ARDS patients in the HMPp was significantly higher than that in the LMPp. The increase of MP during mechanical ventilation in the rats gradually increased lung damage, and CXCL10 and CXCR3 levels in rat plasma gradually increased with the increase of MP. CXCL10 and CXCR3 protein and mRNA expression in the HMPr group and MMPr group was significantly higher than that in the LMPr group ( P < 0.05 ). More mast cells were present in the trachea, bronchus, blood vessels, and lymphatic system in the rat lungs of the HMPr group, and the number of mast cells in the HMPr group ( 13.32 ± 3.27 ) was significantly higher than that in the LMPr group ( 3.25 ± 0.29 ) ( P < 0.05 ). Conclusion. The higher the MP, the more severe the lung injury, and the higher the CXCL10/CXCR3 expression. Therefore, CXCL10/CXCR3 might participate in VILI by mediating mast cell chemotaxis.

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