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 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.

Lack of matrix metalloproteinase-9 worsens ventilator-induced lung injury

2008 ◽  
Vol 294 (3) ◽  
pp. L535-L543 ◽  
Author(s):  
Guillermo M. Albaiceta ◽  
Ana Gutiérrez-Fernández ◽  
Diego Parra ◽  
Aurora Astudillo ◽  
Emilio García-Prieto ◽  
...  
Keyword(s):  
Lung Injury ◽  
Matrix Metalloproteinase ◽  
Cell Count ◽  
Matrix Metalloproteinase 9 ◽  
Lung Mechanics ◽  
Tissue Inhibitors Of Metalloproteinases ◽  
Myeloperoxidase Activity ◽  
Wild Type ◽  
Ventilator Induced Lung Injury ◽  
Metalloproteinase 9

Matrix metalloproteinase-9 (MMP-9) is released by neutrophils at the sites of acute inflammation. This enzyme modulates matrix turnover and inflammatory response, and its activity has been found to be increased after ventilator-induced lung injury. To clarify the role of MMP-9, mice lacking this enzyme and their wild-type counterparts were ventilated for 2 h with high- or low-peak inspiratory pressures (25 and 15 cmH2O, respectively). Lung injury was evaluated by gas exchange, respiratory mechanics, wet-to-dry weight ratio, and histological analysis. The activity of MMP-9 and levels of IL-1β, IL-4, and macrophage inflammatory protein (MIP-2) were measured in lung tissue and bronchoalveolar lavage fluid (BALF). Cell count and myeloperoxidase activity were measured in BALF. There were no differences between wild-type and Mmp9−/− animals after low-pressure ventilation. After high-pressure ventilation, wild-type mice exhibited an increase in MMP-9 in tissue and BALF. Mice lacking MMP-9 developed more severe lung injury than wild-type mice, in terms of impaired oxygenation and lung mechanics, and higher damage in the histological study. These effects correlated with an increase in both cell count and myeloperoxidase activity in the BALF, suggesting an increased neutrophilic influx in response to ventilation. An increase in IL-1β and IL-4 in the BALF only in knockout mice could be responsible for the differences. There were no differences between genotypes in MMP-2, MMP-8, or tissue inhibitors of metalloproteinases. These results show that MMP-9 protects against ventilator-induced lung injury by decreasing alveolar neutrophilic infiltration, probably by modulation of the cytokine response in the air spaces.

scholarly journals Xuebijing Ameliorates Sepsis-Induced Lung Injury by Downregulating HMGB1 and RAGE Expressions in Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Qiao Wang ◽  
Xin Wu ◽  
Xiaowen Tong ◽  
Zhiling Zhang ◽  
Bing Xu ◽  
...  
Keyword(s):  
Lung Injury ◽  
Molecular Mechanisms ◽  
Weight Ratio ◽  
High Mobility ◽  
Dry Weight ◽  
Neutrophil Infiltration ◽  
Beneficial Effects ◽  
Glycation End Products ◽  
Underlying Mechanisms ◽  
Caecal Ligation And Puncture

Xuebijing (XBJ) injection, a traditional Chinese medicine, has been reported as a promising approach in the treatment of sepsis in China. However, its actual molecular mechanisms in sepsis-induced lung injury are yet unknown. Therefore, this study aimed to investigate the beneficial effects of XBJ on inflammation and the underlying mechanisms in a model of caecal ligation and puncture-(CLP-) induced lung injury. The mice were divided into CLP group, CLP+XBJ group (XBJ, 4 mL/kg per 12 hours), and sham group. The molecular and histological examinations were performed on the lung, serum, and bronchoalveolar lavage (BAL) fluid samples of mice at the points of 6, 24, and 48 hours after CLP. The results show that XBJ reduces morphological destruction and neutrophil infiltration in the alveolar space and lung wet/dry weight ratio, which improves mortality of CLP-induced lung injury. Meanwhile, XBJ treatment downregulates high mobility group box protein 1 (HMGB1) and the receptor for advanced glycation end products (RAGE) expression, as well as neutrophil counts, production of IL-1β, IL-6, and TNF-αin the BAL fluids. In conclusion, these results indicate that XBJ may reduce the mortality through inhibiting proinflammatory cytokines secretion mediated by HMGB1/RAGE axis.

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.

scholarly journals β2-Adrenoreceptor blockade improves early posttrauma hyperglycemia and pulmonary injury in obese rats

2014 ◽  
Vol 307 (4) ◽  
pp. H621-H627 ◽  
Author(s):  
Lusha Xiang ◽  
Silu Lu ◽  
Peter N. Mittwede ◽  
John S. Clemmer ◽  
Graham W. Husband ◽  
...  
Keyword(s):  
Lung Injury ◽  
Weight Ratio ◽  
Dry Weight ◽  
Neutrophil Infiltration ◽  
Liver Glycogen ◽  
Severe Trauma ◽  
Obese Patients ◽  
Pulmonary Injury ◽  
Obese Rats ◽  
Novel Method

Early hyperglycemia after trauma increases morbidity and mortality. Insulin is widely used to control posttrauma glucose, but this treatment increases the risk of hypoglycemia. We tested a novel method for early posttrauma hyperglycemia control by suppressing hepatic glycogenolysis via β2-adrenoreceptor blockade [ICI-118551 (ICI)]. We have shown that, after severe trauma, obese Zucker (OZ) rats, similar to obese patients, exhibit increased acute lung injury compared with lean Zucker (LZ) rats. We hypothesized that OZ rats exhibit a greater increase in early posttrauma glucose compared with LZ rats, with the increased posttrauma hyperglycemia suppressed by ICI treatment. Orthopedic trauma was applied to both hindlimbs in LZ and OZ rats. Fasting plasma glucose was then monitored for 6 h with or without ICI (0.2 mg·kg−1·h−1 iv.) treatment. One day after trauma, plasma IL-6 levels, lung neutrophil numbers, myeloperoxidase (MPO) activity, and wet-to-dry weight ratios were measured. Trauma induced rapid hepatic glycogenolysis, as evidenced by decreased liver glycogen levels, and this was inhibited by ICI treatment. Compared with LZ rats, OZ rats exhibited higher posttrauma glucose, IL-6, lung neutrophil infiltration, and MPO activity. Lung wet-to-dry weight ratios were increased in OZ rats but not in LZ rats. ICI treatment reduced the early hyperglycemia, lung neutrophil retention, MPO activity, and wet-to-dry weight ratio in OZ rats to levels comparable with those seen in LZ rats, with no effect on blood pressure or heart rate. These results demonstrate that β2-adrenoreceptor blockade effectively reduces the early posttrauma hyperglycemia, which is associated with decreased lung injury in OZ rats.

scholarly journals Marathoners’ breathing pattern protects against lung injury by mechanical ventilation: a pilot study

2020 ◽  
Author(s):  
Yoshiaki Oshima ◽  
Naoto Okazaki ◽  
Akihiro Otsuki ◽  
Shunsaku Takahashi ◽  
Tomomi Harada ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Lung Injury ◽  
Time Allocation ◽  
Breathing Pattern ◽  
Weight Ratio ◽  
Dry Weight ◽  
Clinical Settings ◽  
Protective Effects ◽  
Ventilator Induced Lung Injury ◽  
Novel Method

Abstract Background: Marathoners use the 2:2 breathing pattern. We hypothesized that this ventilation method may protect against ventilator-induced lung injury.Methods: We studied the 2:2 breathing pattern as a mechanical ventilation mode, by assessing the gas exchange in intact rabbits and the pulmonary protective effects in isolated rabbit lungs. The typical setting of this breathing method was 30 cycles/min of respiratory frequency. The time allocation for one cycle was as follows: 1st inspiratory period, 2nd inspiratory period, 1st expiratory period, and 2nd expiratory period (all 0.3 s long) with intermittent resting periods (all 0.2 s).Results: The 2:2 breathing pattern caused no problems regarding the efficiency of oxygen uptake and carbon dioxide elimination. The wet-to-dry weight ratio of the lung was lower for the proposed 2:2 breathing pattern than with the inversed ratio ventilation (both inspiratory:expiratory ratio 1:1).Conclusions: The marathoners’ breathing pattern may be a novel method to provide protection against ventilator-induced lung injury in clinical settings.

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