Pretreatment with atorvastatin ameliorates lung injury caused by high-pressure/high-tidal-volume mechanical ventilation in isolated normal rabbit lungs

Background Mechanical ventilation can induce organ injury associated with overwhelming inflammatory responses. Excessive activation of poly(adenosine diphosphate-ribose) polymerase enzyme after massive DNA damage may aggravate inflammatory responses. Therefore, the authors hypothesized that the pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase by PJ-34 would attenuate ventilator-induced lung injury. Methods Anesthetized rats were subjected to intratracheal instillation of lipopolysaccharide at a dose of 6 mg/kg. The animals were then randomly assigned to receive mechanical ventilation at either low tidal volume (6 ml/kg) with 5 cm H2O positive end-expiratory pressure or high tidal volume (15 ml/kg) with zero positive end-expiratory pressure, in the presence and absence of intravenous administration of PJ-34. Results The high-tidal-volume ventilation resulted in an increase in poly(adenosine diphosphate-ribose) polymerase activity in the lung. The treatment with PJ-34 maintained a greater oxygenation and a lower airway plateau pressure than the vehicle control group. This was associated with a decreased level of interleukin 6, active plasminogen activator inhibitor 1 in the lung, attenuated leukocyte lung transmigration, and reduced pulmonary edema and apoptosis. The administration of PJ-34 also decreased the systemic levels of tumor necrosis factor alpha and interleukin 6, and attenuated the degree of apoptosis in the kidney. Conclusion The pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase reduces ventilator-induced lung injury and protects kidney function.

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Mechanosensitive cation channel Piezo1 contributes to ventilator-induced lung injury by activating RhoA/ROCK1 in rats

Respiratory Research ◽

10.1186/s12931-021-01844-3 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yang Zhang ◽

Lulu Jiang ◽

Tianfeng Huang ◽

Dahao Lu ◽

Yue Song ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Tidal Volume ◽

Cyclic Stretch ◽

High Tidal Volume ◽

Enzyme Linked Immunosorbent Assay ◽

Sprague Dawley ◽

Ventilator Induced Lung Injury ◽

Enhanced Expression ◽

Underlying Mechanisms

Abstract Background Mechanical ventilation can induce or aggravate lung injury, which is termed ventilator-induced lung injury (VILI). Piezo1 is a key element of the mechanotransduction process and can transduce mechanical signals into biological signals by mediating Ca2+ influx, which in turn regulates cytoskeletal remodeling and stress alterations. We hypothesized that it plays an important role in the occurrence of VILI, and investigated the underlying mechanisms. Methods High tidal volume mechanical ventilation and high magnitude cyclic stretch were performed on Sprague–Dawley rats, and A549 and human pulmonary microvascular endothelial cells, respectively, to establish VILI models. Immunohistochemical staining, flow cytometry, histological examination, enzyme-linked immunosorbent assay, western blotting, quantitative real-time polymerase chain reaction and survival curves were used to assess the effect of Piezo1 on induction of lung injury, as well as the signaling pathways involved. Results We observed that Piezo1 expression increased in the lungs after high tidal volume mechanical ventilation and in cyclic stretch-treated cells. Mechanistically, we observed the enhanced expression of RhoA/ROCK1 in both cyclic stretch and Yoda1-treated cells, while the deficiency or inhibition of Piezo1 dramatically antagonized RhoA/ROCK1 expression. Furthermore, blockade of RhoA/ROCK1 signaling using an inhibitor did not affect Piezo1 expression. GSMTx4 was used to inhibit Piezo1, which alleviated VILI-induced pathologic changes, water content and protein leakage in the lungs, and the induction of systemic inflammatory mediators, and improved the 7-day mortality rate in the model rats. Conclusions These findings indicate that Piezo1 affects the development and progression of VILI through promotion of RhoA/ROCK1 signaling.

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Mechanosensitive Cation Channel Piezo1 Contributes To Ventilator-Induced Lung Injury By Activating RhoA/ROCK1 In Rats

10.21203/rs.3.rs-555235/v1 ◽

2021 ◽

Author(s):

Yang Zhang ◽

Lulu Jiang ◽

Tianfeng Huang ◽

Dahao Lu ◽

Yue Song ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Tidal Volume ◽

Cyclic Stretch ◽

High Tidal Volume ◽

Enzyme Linked Immunosorbent Assay ◽

Sprague Dawley ◽

Reverse Transcription Pcr ◽

Ventilator Induced Lung Injury ◽

Underlying Mechanisms

Abstract Background: Mechanical ventilation can induce or aggravate lung injury, which is termed ventilator‑induced lung injury. Piezo1 is a key element of the mechanotransduction process and can transduce mechanical signals into biological signals by mediating Ca2+ influx, which in turn regulates cytoskeletal remodeling and stress alterations. We hypothesized that it plays an important role in the occurrence of ventilator‑induced lung injury, and we investigated the underlying mechanisms. Methods: High tidal volume mechanical ventilation and high magnitude cyclic stretch were performed on Sprague Dawley rats, and A549 and human pulmonary microvascular endothelial cells, respectively, to establish ventilator‑induced lung injury models. Immunohistochemical staining, flow cytometry, histological examination, enzyme-linked immunosorbent assay, western blotting, quantitative real-time reverse transcription-PCR and survival curves were used to assess the effect of Piezo1 on induction of lung injury, as well as the signaling pathways involved.Results: We observed that Piezo1 expression increased in the lungs after high tidal volume mechanical ventilation and in cyclic stretch-treated cells. Mechanistically, we observed the enhanced expression of RhoA/ROCK1 in both cyclic stretch and Yoda1-treated cells, while the deficiency or inhibition of Piezo1 dramatically antagonized RhoA/ROCK1 expression. Furthermore, blockade of RhoA/ROCK1 signaling using an inhibitor did not affect Piezo1 expression. GSMTx4 was used to inhibit Piezo1, which alleviated ventilator‑induced lung injury-induced pathologic changes, water content and protein leakage in the lungs, and the induction of systemic inﬂammatory mediators, and improved the 7-day mortality rate in the model rats. Conclusions: These findings indicate that Piezo1 affects the development and progression of ventilator‑induced lung injury through promotion of RhoA/ROCK1 signaling.

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High tidal volume mechanical ventilation-induced lung injury in rats is greater after acid instillation than after sepsis-induced acute lung injury, but does not increase systemic inflammation: an experimental study

BMC Anesthesiology ◽

10.1186/1471-2253-11-26 ◽

2011 ◽

Vol 11 (1) ◽

Cited By ~ 15

Author(s):

Jan Willem Kuiper ◽

Frans B Plötz ◽

AB Johan Groeneveld ◽

Jack J Haitsma ◽

Serge Jothy ◽

...

Keyword(s):

Experimental Study ◽

Mechanical Ventilation ◽

Acute Lung Injury ◽

Lung Injury ◽

Tidal Volume ◽

Systemic Inflammation ◽

High Tidal Volume ◽

Ventilation Induced Lung Injury

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Effects of high-tidal-volume mechanical ventilation on the expression of P2X7 receptor and inflammatory response in lung tissue of rats

European Journal of Inflammation ◽

10.1177/2058739218795945 ◽

2018 ◽

Vol 16 ◽

pp. 205873921879594

Author(s):

Jia Jia ◽

Hanyu Qin ◽

Bin Zang

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Tidal Volume ◽

Lung Tissue ◽

Sham Group ◽

Receptor Expression ◽

High Tidal Volume ◽

Caspase 1 ◽

High Tidal Volume Ventilation ◽

Volume Ventilation

Ventilator-induced lung injury is a severe complication mainly caused from mechanical ventilation (MV), associated with the upregulation of inflammation response. The mechanism still remains unclear. This study aims to explore the effects of pathological damage, neutrophil infiltration, expression of P2X7 receptor, and activation of Caspase-1 in lung tissue using a rat model. Sprague Dawley (SD) rats were randomly divided into sham group, conventional MV group, and high-tidal-volume ventilation group and fed with clean water and rat food. The sham group received tracheotomy without MV; conventional MV group was given 7 mL/kg tidal volume ventilation, and high-tidal-volume MV group was given 28 mL/kg tidal volume ventilation. All the rats were sacrificed after 4 h of ventilation or spontaneous breath. Lung wet/dry ratio was measured, and paraffin sections were prepared for pathological injury assessment and immunohistochemistry of P2X7 and myeloperoxidase levels. Lung homogenate was used for Western blot analysis of P2X7 receptor and Caspase-1 levels and real-time polymerase chain reaction (PCR) analysis of P2X7 gene expression level. Compared to sham group and conventional MV group, high-tidal-volume MV led to an increase in lung wet/dry ratio and histology score. High-tidal-volume ventilation also led to chemotaxis of neutrophils. The expression levels of protein and messenger RNA (mRNA) of P2X7 receptor were significantly upregulated. Cleaved-caspase-1 expression was also upregulated. All data provide the evidence that high-tidal-volume MV can lead to lung injury, neutrophils infiltration, and upregulation of cleaved-Caspase-1 level. This result may be related to the upregulation of P2X7 receptor expression.

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Exacerbation of wood smoke-induced acute lung injury by mechanical ventilation using moderately high tidal volume in mice

Respiratory Physiology & Neurobiology ◽

10.1016/j.resp.2007.09.011 ◽

2008 ◽

Vol 160 (1) ◽

pp. 99-108 ◽

Cited By ~ 9

Author(s):

You-Lan Yang ◽

Gau-Jun Tang ◽

Yuh-Lin Wu ◽

Huey-Wen Yien ◽

Tzong-Shyuan Lee ◽

...

Keyword(s):

Mechanical Ventilation ◽

Acute Lung Injury ◽

Lung Injury ◽

Tidal Volume ◽

High Tidal Volume ◽

Wood Smoke

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Lung injury caused by high tidal volume mechanical ventilation and hyperoxia is dependent on oxidant-mediated c-Jun NH2-terminal kinase activation

Journal of Applied Physiology ◽

10.1152/japplphysiol.00539.2011 ◽

2011 ◽

Vol 111 (5) ◽

pp. 1467-1476 ◽

Cited By ~ 14

Author(s):

Patrudu S. Makena ◽

Vijay K. Gorantla ◽

Manik C. Ghosh ◽

Lavanya Bezawada ◽

Louisa Balazs ◽

...

Keyword(s):

Mechanical Ventilation ◽

Lung Injury ◽

Tidal Volume ◽

Prolonged Exposure ◽

Mechanical Stretch ◽

High Tidal Volume ◽

Kinase Activation ◽

Epithelial Cell Apoptosis ◽

Culture Models ◽

Combined Impact

Both prolonged exposure to hyperoxia and large tidal volume mechanical ventilation can each independently cause lung injury. However, the combined impact of these insults is poorly understood. We recently reported that preexposure to hyperoxia for 12 h, followed by ventilation with large tidal volumes, induced significant lung injury and epithelial cell apoptosis compared with either stimulus alone (Makena et al. Am J Physiol Lung Cell Mol Physiol 299: L711–L719, 2010). The upstream mechanisms of this lung injury and apoptosis have not been clearly elucidated. We hypothesized that lung injury in this model was dependent on oxidative signaling via the c-Jun NH2-terminal kinases (JNK). We, therefore, evaluated lung injury and apoptosis in the presence of N-acetyl-cysteine (NAC) in both mouse and cell culture models, and we provide evidence that NAC significantly inhibited lung injury and apoptosis by reducing the production of ROS, activation of JNK, and apoptosis. To confirm JNK involvement in apoptosis, cells treated with a specific JNK inhibitor, SP600125, and subjected to preexposure to hyperoxia, followed by mechanical stretch, exhibited significantly reduced evidence of apoptosis. In conclusion, lung injury and apoptosis caused by preexposure to hyperoxia, followed by high tidal volume mechanical ventilation, induces ROS-mediated activation of JNK and mitochondrial-mediated apoptosis. NAC protects lung injury and apoptosis by inhibiting ROS-mediated activation of JNK and downstream proapoptotic signaling.

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