scholarly journals Ibuprofen Protects Ventilator-Induced Lung Injury by Downregulating Rho-Kinase Activity in Rats

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Liang-Ti Huang ◽  
Chien-Huang Lin ◽  
Hsiu-Chu Chou ◽  
Chung-Ming Chen
Keyword(s):  
Lung Injury ◽  
Protein Expression ◽  
Tidal Volume ◽  
Kinase Activity ◽  
Rho Kinase ◽  
Weight Ratio ◽  
Dry Weight ◽  
High Tidal Volume ◽  
Rhoa Activity ◽  
Ventilator Induced Lung Injury

Background. Ventilator-induced lung injury-(VILI-) induced endothelial permeability is regulated through the Rho-dependent signaling pathway. Ibuprofen inhibits Rho activation in animal models of spinal-cord injury and Alzheimer’s disease. The study aims to investigate ibuprofen effects on high tidal volume associated VILI.Methods. Twenty-eight adult male Sprague-Dawley rats were randomized to receive a ventilation strategy with three different interventions for 2 h: (1) a high-volume zero-positive end-expiratory pressure (PEEP) (HVZP) group; (2) an HVZP + ibuprofen 15 mg/kg group; and (3) an HVZP + ibuprofen 30 mg/kg group. A fourth group without ventilation served as the control group. Rho-kinase activity was determined by ratio of phosphorylated ezrin, radixin, and moesin (p-ERM), substrates of Rho-kinase, to total ERM. VILI was characterized by increased pulmonary protein leak, wet-to-dry weight ratio, cytokines level, and Rho guanine nucleotide exchange factor (GEF-H1), RhoA activity, p-ERM/total ERM, and p-myosin light chain (MLC) protein expression.Results. Ibuprofen pretreatment significantly reduced the HVZP ventilation-induced increase in pulmonary protein leak, wet-to-dry weight ratio, bronchoalveolar lavage fluid interleukin-6 and RANTES levels, and lung GEF-H1, RhoA activity, p-ERM/total ERM, and p-MLC protein expression.Conclusion. Ibuprofen attenuated high tidal volume induced pulmonary endothelial hyperpermeability. This protective effect was associated with a reduced Rho-kinase activity.

Inhibition of matrix metalloproteinase-9 prevents neutrophilic inflammation in ventilator-induced lung injury

2006 ◽  
Vol 291 (4) ◽  
pp. L580-L587 ◽  
Author(s):  
Je Hyeong Kim ◽  
Min Hyun Suk ◽  
Dae Wui Yoon ◽  
Seung Heon Lee ◽  
Gyu Young Hur ◽  
...  
Keyword(s):  
Lung Injury ◽  
Matrix Metalloproteinase ◽  
Tidal Volume ◽  
Weight Ratio ◽  
Dry Weight ◽  
Neutrophil Infiltration ◽  
Neutrophilic Inflammation ◽  
Ventilator Induced Lung Injury ◽  
Metalloproteinase 9 ◽  
Expression And Activity

Neutrophils are considered to play a central role in ventilator-induced lung injury (VILI). However, the pulmonary consequences of neutrophil accumulation have not been fully elucidated. Matrix metalloproteinase-9 (MMP-9) had been postulated to participate in neutrophil transmigration. The purpose of this study was to investigate the role of MMP-9 in the neutrophilic inflammation of VILI. Male Sprague-Dawley rats were divided into three groups: 1) low tidal volume (LVT), 7 ml/kg of tidal volume (VT); 2) high tidal volume (HVT), 30 ml/kg of VT; and 3) HVT with MMP inhibitor (HVT+MMPI). As a MMPI, CMT-3 was administered daily from 3 days before mechanical ventilation. Degree of VILI was assessed by wet-to-dry weight ratio and acute lung injury (ALI) scores. Neutrophilic inflammation was determined from the neutrophil count in the lung tissue and myeloperoxidase (MPO) activity in the bronchoalveolar lavage fluid (BALF). MMP-9 expression and activity were examined by immunohistochemical staining and gelatinase zymography, respectively. The wet-to-dry weight ratio, ALI score, neutrophil infiltration, and MPO activity were increased significantly in the HVT group. However, in the HVT+MMPI group, pretreatment with MMPI decreased significantly the degree of VILI, as well as neutrophil infiltration and MPO activity. These changes correlated significantly with MMP-9 immunoreactivity and MMP-9 activity. Most outcomes were significantly worse in the HVT+MMPI group compared with the LVT group. In conclusion, VILI mediated by neutrophilic inflammation is closely related to MMP-9 expression and activity. The inhibition of MMP-9 protects against the development of VILI through the downregulation of neutrophil-mediated inflammation.

scholarly journals Resolvin D1 Alleviates Ventilator-Induced Lung Injury in Mice by Activating PPARγ/NF-κB Signaling Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Haifa Xia ◽  
Jingxu Wang ◽  
Shujun Sun ◽  
Fuquan Wang ◽  
Yiyi Yang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Protective Effect ◽  
Tidal Volume ◽  
Signaling Pathways ◽  
Lung Tissue ◽  
Fatty Acid Derivative ◽  
High Tidal Volume ◽  
Treatment Modalities ◽  
Resolvin D1 ◽  
Ventilator Induced Lung Injury

As one of the basic treatment modalities in the intensive care unit (ICU), mechanical ventilation can cause or aggravate acute lung injury or ventilator-induced lung injury (VILI). Resolvin D1 (RvD1) is an endogenous polyunsaturated fatty acid derivative with strong anti-inflammatory action. In this study, we explored if RvD1 possesses a protective effect on VILI. Mice were ventilated with high tidal volume (40 mL/kg, HVT) for 4 h and were then intraperitoneally administered RvD1 at the beginning of high tidal volume ventilation and given GW9662 (a PPAR-γ antagonist) intraperitoneally 30 min before ventilation. RvD1 attenuated VILI, as evidenced by improved oxygenation and reduced histological injury, compared with HVT -induced lung injury. Similarly, it could ameliorate neutrophil accumulation and production of proinflammatory cytokines in lung tissue. In contrast, the protective effect of RvD1 on lung tissue could be reversed by GW9662. RvD1 mitigated VILI by activating peroxisome proliferator-activated receptor gamma (PPAR-γ) and inhibiting nuclear factor-kappa B (NF-κB) signaling pathways in mice. In conclusion, RvD1 could reduce the inflammatory response in VILI by activating PPAR-γ and inhibiting NF-κB signaling pathways.

scholarly journals Inhibition of Poly(Adenosine Diphosphate–Ribose) Polymerase Attenuates Ventilator-induced Lung Injury

2008 ◽  
Vol 108 (2) ◽  
pp. 261-268 ◽  
Author(s):  
Rosanna Vaschetto ◽  
Jan W. Kuiper ◽  
Shyh Ren Chiang ◽  
Jack J. Haitsma ◽  
Jonathan W. Juco ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Tidal Volume ◽  
Interleukin 6 ◽  
Inflammatory Responses ◽  
Adenosine Diphosphate ◽  
High Tidal Volume ◽  
Positive End Expiratory Pressure ◽  
Ventilator Induced Lung Injury ◽  
Pharmacologic Inhibition

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.

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

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.

scholarly journals Alveolar Overdistension as a Cause of Lung Injury: Differences among Three Animal Species

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Manuel García-Delgado ◽  
Inés Navarrete-Sánchez ◽  
Virginia Chamorro-Marín ◽  
Juan Carlos Díaz-Monrové ◽  
Javier Esquivias ◽  
...  
Keyword(s):  
Tidal Volume ◽  
Animal Species ◽  
Tension Pneumothorax ◽  
Weight Ratio ◽  
Dry Weight ◽  
In Vivo Studies ◽  
High Tidal Volume ◽  
Alveolar Collapse ◽  
Alveolar Overdistension

This study analyses characteristics of lung injuries produced by alveolar overdistension in three animal species. Mechanical ventilation at normal tidal volume (10 mL/Kg) and high tidal volume (50 mL/Kg) was applied for 30 min in each species. Data were gathered on wet/dry weight ratio, histological score, and area of alveolar collapse. Five out of six rabbits with high tidal volume developed tension pneumothorax, and the rabbit results were therefore not included in the histological analysis. Lungs from the pigs and rats showed minimal histological lesions. Pigs ventilated with high tidal volume had significantly greater oedema, higher neutrophil infiltration, and higher percentage area of alveolar collapse than rats ventilated with high tidal volume. We conclude that rabbits are not an appropriate species for in vivo studies of alveolar overdistension due to their fragility. Although some histological lesions are observed in pigs and rats, the lesions do not appear to be relevant.

Effect of Recombinant Human Thrombomodulin on Ventilator-Induced Lung Injury in Septic Rats

2021 ◽  
Author(s):  
Yoshiaki Iwashita ◽  
Zhang Erquan ◽  
Hirofumi Sawada ◽  
Masako Kawai ◽  
Junko Maruyama ◽  
...  
Keyword(s):  
Lung Injury ◽  
Tidal Volume ◽  
Cecal Ligation ◽  
Male Rats ◽  
High Tidal Volume ◽  
Mrna Levels ◽  
Protein Levels ◽  
Ventilator Induced Lung Injury ◽  
Tidal Ventilation ◽  
Recombinant Thrombomodulin

Abstract Background: High tidal ventilation with inflammation causes ventilator-induced lung injury (VILI). We previously found that recombinant thrombomodulin (rTM) has a protective effect regarding non-septic VILI caused by high-tidal-volume (HV) ventilation with high oxygen levels. This study aimed to investigate the preventive effect of rTM on VILI caused by sepsis and HV ventilation. Methods: A total of 46 adult male rats were subcutaneously administered either 3mg/kg of rTM or saline. Twelve hours later, the rats were underwent cecal ligation and puncture (CLP). At 2 h after this procedure, the rats were placed on a ventilator set at either low tidal volume [(LV) 6 ml/kg] or high tidal volume (HV 35 ml/kg) ventilation for another 2 h. Results: After 2 h of mechanical ventilation, the PaO2 was significantly lower and BALF protein was significantly higher in HV rats than in LV rats. The rTM did not improve oxygenation or BALF protein levels. Also in HV rats, lung tissue interleukin-6 and monocyte chemotactic protein-1 mRNA levels were significantly higher in the rTM-treated rats.Conclusion: rTM does not improve oxygenation in a non-DIC, CLP-pretreated, high-tidal-ventilation rat model.

scholarly journals Rap1 mediates protective effects of iloprost against ventilator-induced lung injury

2009 ◽  
Vol 107 (6) ◽  
pp. 1900-1910 ◽  
Author(s):  
Anna A. Birukova ◽  
Panfeng Fu ◽  
Junjie Xing ◽  
Konstantin G. Birukov
Keyword(s):  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Tidal Volume ◽  
Evans Blue ◽  
High Tidal Volume ◽  
Protective Effects ◽  
Ventilator Induced Lung Injury ◽  
High Tidal Volume Ventilation ◽  
Volume Ventilation

Prostaglandin I2 (PGI2) has been shown to attenuate vascular constriction, hyperpermeability, inflammation, and acute lung injury. However, molecular mechanisms of PGI2 protective effects on pulmonary endothelial cells (EC) are not well understood. We tested a role of cAMP-activated Epac-Rap1 pathway in the barrier protective effects of PGI2 analog iloprost in the murine model of ventilator-induced lung injury. Mice were treated with iloprost (2 μg/kg) after onset of high tidal volume ventilation (30 ml/kg, 4 h). Bronchoalveolar lavage, histological analysis, and measurements of Evans blue accumulation were performed. In vitro, microvascular EC barrier function was assessed by morphological analysis of agonist-induced gap formation and monitoring of Rho pathway activation and EC permeability. Iloprost reduced bronchoalveolar lavage protein content, neutrophil accumulation, capillary filtration coefficient, and Evans blue albumin extravasation caused by high tidal volume ventilation. Small-interfering RNA-based Rap1 knockdown inhibited protective effects of iloprost. In vitro, iloprost increased barrier properties of lung microvascular endothelium and alleviated thrombin-induced EC barrier disruption. In line with in vivo results, Rap1 depletion attenuated protective effects of iloprost in the thrombin model of EC permeability. These data describe for the first time protective effects for Rap1-dependent signaling against ventilator-induced lung injury and pulmonary endothelial barrier dysfunction.

High tidal volume ventilation induces lung injury after hepatic ischemia-reperfusion

2007 ◽  
Vol 292 (3) ◽  
pp. L625-L631 ◽  
Author(s):  
Shuhei Ota ◽  
Kyota Nakamura ◽  
Takuya Yazawa ◽  
Yosuke Kawaguchi ◽  
Yasuko Baba ◽  
...  
Keyword(s):  
Lung Injury ◽  
Tidal Volume ◽  
Ischemia Reperfusion ◽  
Weight Ratio ◽  
High Tidal Volume ◽  
Sham Operation ◽  
Liver Ischemia ◽  
High Tidal Volume Ventilation ◽  
Volume Ventilation ◽  
Tnf Α

Ischemia-reperfusion not only damages the affected organ but also leads to remote organ injuries. Hepatic inflow interruption usually occurs during hepatic surgery. To investigate the influence of liver ischemia-reperfusion on lung injury and to determine the contribution of tidal volume settings on liver ischemia-reperfusion-induced lung injury, we studied anesthetized and mechanically ventilated rats in which the hepatic inflow was transiently interrupted twice for 15 min. Two tidal volumes, 6 ml/kg as a low tidal volume (IR-LT) and 24 ml/kg as a high tidal volume (IR-HT), were assessed after liver ischemia-reperfusion, as well as after a sham operation, 6 ml/kg (NC-LT) and 24 ml/kg (NC-HT). Both the IR-HT and IR-LT groups had a gradual decline in the systemic blood pressure and a significant increase in plasma TNF-α concentrations. Of the four groups, only the IR-HT group developed lung injury, as assessed by an increase in the lung wet-to-dry weight ratio, the presence of significant histopathological changes, such as perivascular edema and intravascular leukocyte aggregation, and an increase in the bronchoalveolar lavage fluid TNF-α concentration. Furthermore, only in the IR-HT group was airway pressure increased significantly during the 6-h reperfusion period. These findings suggest that liver ischemia-reperfusion caused systemic inflammation and that lung injury is triggered when high tidal volume ventilation follows liver ischemia-reperfusion.

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

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.

scholarly journals Continuous Negative Abdominal Pressure Reduces Ventilator-induced Lung Injury in a Porcine Model

2018 ◽  
Vol 129 (1) ◽  
pp. 163-172 ◽  
Author(s):  
Takeshi Yoshida ◽  
Doreen Engelberts ◽  
Gail Otulakowski ◽  
Bhushan Katira ◽  
Martin Post ◽  
...  
Keyword(s):  
Lung Injury ◽  
Interleukin 6 ◽  
Weight Ratio ◽  
Transpulmonary Pressure ◽  
Dry Weight ◽  
Esophageal Pressure ◽  
Abdominal Pressure ◽  
Impedance Tomography ◽  
Ventilator Induced Lung Injury ◽  
Novel Approach

Abstract Background In supine patients with acute respiratory distress syndrome, the lung typically partitions into regions of dorsal atelectasis and ventral aeration (“baby lung”). Positive airway pressure is often used to recruit atelectasis, but often overinflates ventral (already aerated) regions. A novel approach to selective recruitment of dorsal atelectasis is by “continuous negative abdominal pressure.” Methods A randomized laboratory study was performed in anesthetized pigs. Lung injury was induced by surfactant lavage followed by 1 h of injurious mechanical ventilation. Randomization (five pigs in each group) was to positive end-expiratory pressure (PEEP) alone or PEEP with continuous negative abdominal pressure (−5 cm H2O via a plexiglass chamber enclosing hindlimbs, pelvis, and abdomen), followed by 4 h of injurious ventilation (high tidal volume, 20 ml/kg; low expiratory transpulmonary pressure, −3 cm H2O). The level of PEEP at the start was ≈7 (vs. ≈3) cm H2O in the PEEP (vs. PEEP plus continuous negative abdominal pressure) groups. Esophageal pressure, hemodynamics, and electrical impedance tomography were recorded, and injury determined by lung wet/dry weight ratio and interleukin-6 expression. Results All animals survived, but cardiac output was decreased in the PEEP group. Addition of continuous negative abdominal pressure to PEEP resulted in greater oxygenation (Pao2/fractional inspired oxygen 316 ± 134 vs. 80 ± 24 mmHg at 4 h, P = 0.005), compliance (14.2 ± 3.0 vs. 10.3 ± 2.2 ml/cm H2O, P = 0.049), and homogeneity of ventilation, with less pulmonary edema (≈10% less) and interleukin-6 expression (≈30% less). Conclusions Continuous negative abdominal pressure added to PEEP reduces ventilator-induced lung injury in a pig model compared with PEEP alone, despite targeting identical expiratory transpulmonary pressure.

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