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

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.

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Experimental Ventilator-induced Lung Injury

Anesthesiology ◽

10.1097/aln.0b013e31819fcba9 ◽

2009 ◽

Vol 110 (6) ◽

pp. 1341-1347 ◽

Cited By ~ 27

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.

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

10.21203/rs.3.rs-139231/v1 ◽

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.

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ADAM17 inhibition prevents neutrophilia and lung injury in a mouse model of Covid-19

10.1101/2021.04.10.439288 ◽

2021 ◽

Author(s):

Nathaniel L. Lartey ◽

Salvador Valle-Reyes ◽

Hilda Vargas-Robles ◽

Karina E. Jiménez-Camacho ◽

Idaira M. Guerrero-Fonseca ◽

...

Keyword(s):

Lung Injury ◽

Mouse Model ◽

Inflammatory Responses ◽

Specific Treatment ◽

Lung Damage ◽

Poly I:C ◽

Leukocyte Infiltration ◽

Vascular Congestion ◽

Current Therapies ◽

Endothelial Adhesion Molecules

Severe coronavirus disease 2019 (Covid-19) is characterized by lung injury, cytokine storm and increased neutrophil-to-lymphocyte ratio (NLR). Current therapies focus on reducing viral replication and inflammatory responses, but no specific treatment exists to prevent the development of severe Covid-19 in infected individuals. Angiotensin-converting enzyme-2 ACE-2) is the receptor for SARS-CoV-2, the virus causing Covid-19, but it is also critical for maintaining the correct functionality of lung epithelium and endothelium. Coronaviruses induce activation of a disintegrin and metalloprotease 17 (ADAM17) and shedding of ACE-2 from the cell surface resulting in exacerbated inflammatory responses. Thus, we hypothesized that ADAM17 inhibition ameliorates Covid-19-related lung inflammation. We employed a pre-clinical mouse model using intra-tracheal instillation of a combination of polyinosinic:polycytidylic acid (poly-I:C) and the receptor-binding domain of the SARS-CoV-2 spike protein (RBD-S) to mimic lung damage associated with Covid-19. Histological analysis of inflamed mice confirmed the expected signs of lung injury including edema, fibrosis, vascular congestion and leukocyte infiltration. Moreover, inflamed mice also showed an increased NLR as observed in critically ill Covid-19 patients. Administration of the ADAM17 inhibitors apratastat and TMI-1 significantly improved lung histology and prevented leukocyte infiltration. Reduced leukocyte recruitment could be explained by reduced production of pro-inflammatory cytokines and lower levels of the endothelial adhesion molecules ICAM-1 and VCAM-1. Additionally, the NLR was significantly reduced by ADAM17 inhibition. Thus, we propose inhibition of ADAM17 as a novel promising treatment strategy in SARS-CoV-2-infected individuals to prevent the progression towards severe Covid-19.

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Genetic and pharmacologic inhibition of Tpl2 kinase is protective in a mouse model of ventilator-induced lung injury

Intensive Care Medicine Experimental ◽

10.1186/2197-425x-2-15 ◽

2014 ◽

Vol 2 (1) ◽

pp. 15 ◽

Cited By ~ 3

Author(s):

Evangelos Kaniaris ◽

Katerina Vaporidi ◽

Eleni Vergadi ◽

Emmanuel E Theodorakis ◽

Eumorfia Kondili ◽

...

Keyword(s):

Lung Injury ◽

Mouse Model ◽

Ventilator Induced Lung Injury ◽

Pharmacologic Inhibition

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/3715037 ◽

2017 ◽

Vol 2017 ◽

pp. 1-14 ◽

Cited By ~ 13

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.

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The Relative Roles Of Volutrauma And Atelectrauma In A Mouse Model Of Ventilator-induced Lung Injury

10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a2157 ◽

2010 ◽

Author(s):

Adrian S. Seah ◽

Kara A. Grant ◽

Gilman B. Allen ◽

Minara Aliyeva ◽

Jason H.T. Bates

Keyword(s):

Lung Injury ◽

Mouse Model ◽

Ventilator Induced Lung Injury

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

Intensive Care Medicine ◽

10.1007/s00134-001-1177-2 ◽

2002 ◽

Vol 28 (2) ◽

pp. 196-203 ◽

Cited By ~ 20

Author(s):

Silvio Sibilla ◽

Stefano Tredici ◽

Giuliana Porro ◽

Manuela Irace ◽

Massimiliano Guglielmi ◽

...

Keyword(s):

Lung Injury ◽

Respiratory System ◽

Lung Damage ◽

Ventilator Induced Lung Injury

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

BioMed Research International ◽

10.1155/2022/6803154 ◽

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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NADPH Oxidase 4 Signaling in a Ventilator-Induced Lung Injury Mouse Model

10.21203/rs.3.rs-104053/v1 ◽

2020 ◽

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 ◽

Nadph Oxidase 4 ◽

Ventilator Induced Lung Injury ◽

Oxygen Fraction ◽

Cell Counts ◽

The Relationship

Abstract BackgroundFor patients with acute respiratory distress syndrome (ARDS), a ventilator is essential to supply oxygen to tissues, but it may also cause lung damage. In this study, we investigated the role of NOX4 in lung injury using NOX4 knockout (KO) mice and NOX4 inhibitors in a ventilator-induced lung injury (VILI) model.MethodsWild-type male C57BL/6J mice and NOX4 KO male mice were divided into five groups: (1) control group: wild-type (WT) mice + non-ventilator; (2) high tidal ventilation (HTV) group: WT mice + HTV; (3) NOX4 KO group: NOX4 KO + non-ventilator; (4) NOX4 KO with HTV group: NOX4 KO mice + HTV; (5) NOX4 inhibitor group: WT mice + HTV + post-treatment (anti-GKT 137831 inhibitor). In the VILI model, the supine position was maintained at 24 mL/kg volume, 0 cm H2O PEEP, 100/min respiratory rate, and 0.21 inspired oxygen fraction. In the NOX4 inhibitor group, 50 μL anti-GKT 137831 inhibitor was injected intraperitoneally, 2 h after ventilator use. After 5 h of HTV, mice in the ventilator group were euthanized, and their lung tissues were obtained for further analysis. 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.ResultsCell counts from BALFs were significantly lower (p<0.01) in the NOX4 KO with HTV group compared to that in the HTV group. In the NOX4 inhibitor group, cell counts and protein concentrations were significantly lower than those in the HTV group (both, p<0.001). In the NOX4 KO mouse group and the NOX4 inhibitor group, EphA2 levels were significantly lower than those in the HTV group (both, p<0.001). In patients with respiratory disease, NOX4 levels were significantly higher in patients with pneumonia and patients who received ventilator treatment in the intensive care unit.ConclusionsIn the VILI model, NOX4 expression is significantly associated with Eph-ephrin signaling. It may be possible to block VILI using NOX4 antibodies.

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