scholarly journals Does lack ofglutathione peroxidase 1gene expression exacerbate lung injury induced by neonatal hyperoxia in mice?

2017 ◽  
Vol 313 (1) ◽  
pp. L115-L125 ◽  
Author(s):  
Sheena Bouch ◽  
Megan O’Reilly ◽  
Judy B. de Haan ◽  
Richard Harding ◽  
Foula Sozo
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Lung Injury ◽  
Lung Tissue ◽  
Immune Cells ◽  
Lavage Fluid ◽  
Supplemental Oxygen ◽  
Heme Oxygenase 1 ◽  
Long Term Effects ◽  
Glutathione Peroxidase 1

Supplemental oxygen (O2) increases the risk of lung injury in preterm infants, owing to an immature antioxidant system. Our objective was to determine whether impairing antioxidant defense by decreasing glutathione peroxidase 1 ( GPx1) gene expression increases the injurious effects of hyperoxia (Hyp). GPx1+/+and GPx1−/−C57Bl/6J mice were exposed to 21% O2(Air) or 40% O2(Hyp) from birth to postnatal day 7 (P7d); they were euthanized on P7d or maintained in air until adulthood [postnatal day 56 (P56d)] to assess short-term and long-term effects, respectively. We assessed lung architecture, three markers of pulmonary oxidative stress (P7d, P56d), macrophages in lung tissue (P7d), immune cells in bronchoalveolar lavage fluid (BALF; P56d), and GPx1-4 and catalase gene expression in lung tissue (P7d, P56d). On P7d, macrophages were decreased by lack of GPx1 expression and further decreased by hyperoxia. GPx1 expression was increased in GPx1+/+Hyp mice and decreased in both GPx1−/−groups. On P56d, heme oxygenase-1 was increased by hyperoxia when GPx1 was absent. There were significantly more immune cells from Hyp groups than from the GPx1+/+Air group and a greater proportion of lymphocytes in GPx1−/−Hyp mice. GPx1 expression was significantly decreased in GPx1−/−mice; GPx2-4 and catalase expression was increased in GPx1−/−Hyp mice compared with other groups. Tissue fraction was decreased in GPx1−/−Air mice; bronchiolar smooth muscle was decreased in GPx1−/−mice. GPx1 does not clearly exacerbate hyperoxia-induced increases in oxidative stress or lung injury but may alter pulmonary immune function. Increased expression of GPx2-4 and catalase in GPx1−/−Hyp mice suggests gene redundancy within the model.

Neonatal exposure to mild hyperoxia causes persistent increases in oxidative stress and immune cells in the lungs of mice without altering lung structure

2015 ◽  
Vol 309 (5) ◽  
pp. L488-L496 ◽  
Author(s):  
Sheena Bouch ◽  
Megan O'Reilly ◽  
Richard Harding ◽  
Foula Sozo
Keyword(s):  
Oxidative Stress ◽  
Immune Cells ◽  
Respiratory Illness ◽  
Lavage Fluid ◽  
Supplemental Oxygen ◽  
Heme Oxygenase 1 ◽  
Lung Structure ◽  
Increased Risk ◽  
Neonatal Hyperoxia ◽  
Tissue Fraction

Preterm infants often require supplemental oxygen due to lung immaturity, but hyperoxia can contribute to an increased risk of respiratory illness later in life. Our aim was to compare the effects of mild and moderate levels of neonatal hyperoxia on markers of pulmonary oxidative stress and inflammation and on lung architecture; both immediate and persistent effects were assessed. Neonatal mice (C57BL6/J) were raised in either room air (21% O2), mild (40% O2), or moderate (65% O2) hyperoxia from birth until postnatal day 7 (P7d). The mice were killed at either P7d (immediate effects) or lived in air until adulthood (P56d, persistent effects). We enumerated macrophages in lung tissue at P7d and immune cells in bronchoalveolar lavage fluid (BALF) at P56d. At P7d and P56d, we assessed pulmonary oxidative stress [ heme oxygenase-1 ( HO-1) and nitrotyrosine staining] and lung architecture. The data were interrogated for sex differences. At P7d, HO-1 gene expression was greater in the 65% O2 group than in the 21% O2 group. At P56d, the area of nitrotyrosine staining and number of immune cells were greater in the 40% O2 and 65% O2 groups relative to the 21% O2 group. Exposure to 65% O2, but not 40% O2, led to larger alveoli and lower tissue fraction in the short term and to persistently fewer bronchiolar-alveolar attachments. Exposure to 40% O2 or 65% O2 causes persistent increases in pulmonary oxidative stress and immune cells, suggesting chronic inflammation within the adult lung. Unlike 65% O2, 40% O2 does not affect lung architecture.

scholarly journals Differential Oxidative Stress Responses to D-Galactosamine-Lipopolysaccharide Hepatotoxicity Based on Real Time PCR Analysis of Selected Oxidant/Antioxidant and Apoptotic Gene Expressions in Rat

2011 ◽  
pp. 549-558 ◽  
Author(s):  
N. LEKIĆ ◽  
D. ČERNÝ ◽  
A. HOŘÍNEK ◽  
Z. PROVAZNÍK ◽  
J. MARTÍNEK ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Stress Responses ◽  
Caspase 3 ◽  
Histological Evaluation ◽  
Pcr Analysis ◽  
Heme Oxygenase 1 ◽  
Gene Expressions ◽  
Glutathione Peroxidase 1 ◽  
Apoptotic Pathways

Oxidative stress and apoptosis are proposed mechanisms of cellular injury in studies of xenobiotic hepatotoxicity. This study is focused on addressing the mutual relationship and early signals of these mechanisms in the D-galactosamine and lipopolysaccharide (D-GalN/LPS) hepatotoxicity model, with the help of standard liver function and biochemistry tests, histology, and measurement of gene expression by RT-PCR. Intraperitoneal injection of 400 mg/kg D-GalN and 50 μg/kg LPS was able to induce hepatotoxicity in rats, as evidenced by significant increases in liver enzymes (ALT, AST) and raised bilirubin levels in plasma. Heme oxygenase-1 and nitric oxide synthase-2 gene expressions were significantly increased, along with levels of their products, bilirubin and nitrite. The gene expression of glutathione peroxidase 1 remained unchanged, whereas a decrease in superoxide dismutase 1 gene expression was noted. Furthermore, the significant increase in the gene expression of apoptotic genes Bid, Bax and caspase-3 indicate early activation of apoptotic pathways, which was confirmed by histological evaluation. In contrast, the measured caspase-3 activity remained unchanged. Overall, the results have revealed differential oxidative stress and apoptotic responses, which deserves further investigations in this hepatotoxicity model.

scholarly journals Computational genomic analysis of the lung tissue microenvironment in COVID-19 patients

2021 ◽  
Author(s):  
Krithika Bhuvaneshwar ◽  
Subha Madhavan ◽  
Yuriy Gusev
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Side Effects ◽  
Viral Infection ◽  
Lung Tissue ◽  
Immune Cells ◽  
Long Term Effects ◽  
Tissue Microenvironment ◽  
The World

The coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-CoV-2 virus has affected over 170 million people, and caused over 3.5 million deaths throughout the world as of May 2021. Although over 150 million people around the world have recovered from this disease, the long term effects of the disease are still under study. A year after the start of the pandemic, data from COVID-19 recovered patients shows multiple organs affected with a broad spectrum of manifestations. Long term effects of SARS-CoV-2 infection includes fatigue, chest pain, cellular damage, and robust innate immune response with inflammatory cytokine production. More clinical studies and trials are needed to not only document, but also to understand the factors that predispose certain people to the long term side effects of his infection. In this manuscript, our goal was to explore the multidimensional landscape of infected lung tissue microenvironment to better understand complex interactions between SARS-CoV-2 viral infection , immune response and the lungs microbiome of COVID-19 patients. Each sample was analyzed with several machine learning tools allowing simultaneous detection and quantification of viral RNA amount at genome and gene level; human gene expression and fractions of major types of immune cells, as well as metagenomic analysis of bacterial and viral abundance. To contrast and compare specific viral response to SARS-COV-2 we have analyzed deep sequencing data from additional cohort of patients infected with NL63 strain of corona virus. Correlation analysis of three types of measurements i.e. fraction of viral RNA, Human RNA and bacterial RNA (metagenomic analysis), showed significant correlation between viral load as well as level of specific viral gene expression with the fractions of immune cells present in lung lavage as well as with abundance of major fractions of lung microbiome in COVID-19 patients. Our exploratory study has provided novel insights into complex regulatory signaling interactions and correlative patterns between the viral infection, inhibition of innate and adaptive immune response as well as microbiome landscape of the lung tissue. These initial findings could provide better understanding of the diverse dynamics of immune response and the side effects of the SARS-CoV-2 infection.

scholarly journals Tomatidine Improves Pulmonary Inflammation in Mice with Acute Lung Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Wen-Chung Huang ◽  
Shu-Ju Wu ◽  
Ya-Ling Chen ◽  
Chwan-Fwu Lin ◽  
Chian-Jiun Liou
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Tissue ◽  
Inflammatory Cytokine ◽  
Animal Experiments ◽  
Intratracheal Instillation ◽  
Lung Epithelial Cells ◽  
Mitogen Activated Protein Kinase ◽  
Heme Oxygenase 1

Tomatidine, which is isolated from green tomato, can ameliorate inflammation and oxidative stress in cells and animal experiments and has been shown to improve airway inflammation in a murine model of asthma. Here, we investigated whether tomatidine can ameliorate acute lung injury in mice. Mice were given tomatidine by intraperitoneal injection for 7 consecutive days, and then, lung injury was induced via intratracheal instillation of lipopolysaccharide (LPS). Tomatidine reduced inflammatory cytokine expressions in bronchoalveolar lavage fluid (BALF), attenuated neutrophil infiltration in the BALF and lung tissue, increased superoxide dismutase activity and glutathione levels, and alleviated myeloperoxidase expression in the lung tissue of mice with lung injury. Tomatidine also decreased inflammatory cytokine and chemokine gene expression in inflammatory lungs and attenuated the phosphorylation of mitogen-activated protein kinase and nuclear factor kappa B. Furthermore, tomatidine enhanced the production of heme oxygenase-1, decreased the secretion of inflammatory cytokines and chemokines in LPS-stimulated lung epithelial cells, and attenuated THP-1 monocyte adhesion. Our findings suggest that tomatidine attenuates oxidative stress and inflammation, improving acute lung injury in mice.

Endothelial Poldip2 regulates sepsis-induced lung injury via Rho pathway activation

2021 ◽  
Author(s):  
Elena V Dolmatova ◽  
Steven J Forrester ◽  
Keke Wang ◽  
Ziwei Ou ◽  
Holly C Williams ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Injury ◽  
Lung Tissue ◽  
Rho Gtpase ◽  
Endothelial Activation ◽  
Altered Expression ◽  
Knock Out ◽  
Knock Down ◽  
Leucocyte Infiltration

Abstract Aims Sepsis-induced lung injury is associated with significant morbidity and mortality. Previously, we showed that heterozygous deletion of polymerase δ-interacting protein 2 (Poldip2) was protective against sepsis-induced lung injury. Since endothelial barrier disruption is thought to be the main mechanism of sepsis-induced lung injury, we sought to determine if the observed protection was specifically due to the effect of reduced endothelial Poldip2. Methods and results Endothelial-specific Poldip2 knock-out mice (EC−/−) and their wild-type littermates (EC+/+) were injected with saline or lipopolysaccharide (18 mg/kg) to model sepsis-induced lung injury. At 18 h post-injection mice, were euthanized and bronchoalveolar lavage (BAL) fluid and lung tissue were collected to assess leucocyte infiltration. Poldip2 EC−/− mice showed reduced lung leucocyte infiltration in BAL (0.21 ± 0.9×106 vs. 1.29 ± 1.8×106 cells/mL) and lung tissue (12.7 ± 1.8 vs. 23 ± 3.7% neutrophils of total number of cells) compared to Poldip2 EC+/+ mice. qPCR analysis of the lung tissue revealed a significantly dampened induction of inflammatory gene expression (TNFα 2.23 ± 0.39 vs. 4.15 ± 0.5-fold, IκBα 4.32 ± 1.53 vs. 8.97 ± 1.59-fold), neutrophil chemoattractant gene expression (CXCL1 68.8 ± 29.6 vs. 147 ± 25.7-fold, CXCL2 65 ± 25.6 vs. 215 ± 27.3-fold) and a marker of endothelial activation (VCAM1 1.25 ± 0.25 vs. 3.8 ± 0.38-fold) in Poldip2 EC−/− compared to Poldip2 EC+/+ lungs. An in vitro model using human pulmonary microvascular endothelial cells was used to assess the effect of Poldip2 knock-down on endothelial activation and permeability. TNFα-induced endothelial permeability and VE-cadherin disruption were significantly reduced with siRNA-mediated knock-down of Poldip2 (5 ± 0.5 vs. 17.5 ± 3-fold for permeability, 1.5 ± 0.4 vs. 10.9 ± 1.3-fold for proportion of disrupted VE-cadherin). Poldip2 knock-down altered expression of Rho-GTPase-related genes, which correlated with reduced RhoA activation by TNFα (0.94 ± 0.05 vs. 1.29 ± 0.01 of relative RhoA activity) accompanied by redistribution of active-RhoA staining to the centre of the cell. Conclusion Poldip2 is a potent regulator of endothelial dysfunction during sepsis-induced lung injury, and its endothelium-specific inhibition may provide clinical benefit.

Rgx365, a Rare Protopanaxatriol-Type Ginsenoside Fraction from Black Ginseng, Suppresses Inflammatory Gene iNOS via the Iinhibition of p-STAT-1 and NF-κB

2020 ◽  
Vol 48 (05) ◽  
pp. 1091-1102
Author(s):  
So Yeon Jeong ◽  
Ji-Eun Kim ◽  
Gyu-Yong Song ◽  
Jong-Sup Bae
Keyword(s):  
Lung Tissue ◽  
Lavage Fluid ◽  
Heme Oxygenase 1 ◽  
Inos Protein ◽  
Protein Levels ◽  
Rna Transfection ◽  
Inos Protein Expression ◽  
Black Ginseng ◽  
Cox 2 ◽  
Human Pulmonary Artery

Black ginseng (BG), which is ginseng that has been steamed and dried nine times, and its main protopanaxatriol-type ginsenosides Rg4, Rg6, Rh4, and Rg2 have been reported to exhibit various forms of biological activity, including antiseptic, antidiabetic, wound-healing, immune-stimulatory, and anti-oxidant activity. The aim of the this study was to examine the effects of [Formula: see text] (a rare protopanaxatriol-type ginsenoside fraction; Rg2, Rg4, Rg6, Rh1, and Rh4) on heme oxygenase-1 (HO-1) induction and on the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-)2 in lipopolysaccharide (LPS)-activated human pulmonary artery endothelial cells (HPAECs). [Formula: see text] was tested to determine its effect on iNOS protein expression and inflammatory markers (interleukin [IL]-1[Formula: see text] and tumor necrosis factor [TNF]-[Formula: see text] in the lung tissue of LPS-treated mice. The results showed that [Formula: see text] induced the expression of HO-1, reduced LPS-activated NF-[Formula: see text]B-luciferase activity, and inhibited iNOS/NO and COX-2/PGE2, which contributed to the inhibition of STAT-1 phosphorylation. In particular, [Formula: see text] induced the translocation of Nrf2 from the cytosol to the nucleus by increasing Nrf2-ARE activity and decreased IL-1[Formula: see text] production in LPS-activated HPAECs. This reduction in iNOS/NO expression due to [Formula: see text] was reversed by siHO-1 RNA transfection. In LPS-treated mice, [Formula: see text] significantly reduced lung tissue iNOS protein levels and TNF-[Formula: see text] levels in the bronchoalveolar lavage fluid. In conclusion, these findings indicate that [Formula: see text] has a critical anti-inflammatory effect due to its ability to regulate iNOS via the inhibition of p-STAT-1 and NF-[Formula: see text]B, and thus it may be suitable for the treatment of inflammatory disease.

A Metabolomic Approach to the Pathogenesis of Ventilator-induced Lung Injury

2014 ◽  
Vol 120 (3) ◽  
pp. 694-702 ◽  
Author(s):  
José L. Izquierdo-García ◽  
Shama Naz ◽  
Nicolás Nin ◽  
Yeny Rojas ◽  
Marcela Erazo ◽  
...  
Keyword(s):  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Tidal Volume ◽  
Lung Tissue ◽  
Metabolic Profiling ◽  
Metabolic Profile ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Positive End Expiratory Pressure ◽  
Ventilator Induced Lung Injury

Abstract Background: Global metabolic profiling using quantitative nuclear magnetic resonance spectroscopy (MRS) and mass spectrometry (MS) is useful for biomarker discovery. The objective of this study was to discover biomarkers of acute lung injury induced by mechanical ventilation (ventilator-induced lung injury [VILI]), by using MRS and MS. Methods: Male Sprague–Dawley rats were subjected to two ventilatory strategies for 2.5 h: tidal volume 9 ml/kg, positive end-expiratory pressure 5 cm H2O (control, n = 14); and tidal volume 25 ml/kg and positive end-expiratory pressure 0 cm H2O (VILI, n = 10). Lung tissue, bronchoalveolar lavage fluid, and serum spectra were obtained by high-resolution magic angle spinning and 1H-MRS. Serum spectra were acquired by high-performance liquid chromatography coupled to quadupole-time of flight MS. Principal component and partial least squares analyses were performed. Results: Metabolic profiling discriminated characteristics between control and VILI animals. As compared with the controls, animals with VILI showed by MRS higher concentrations of lactate and lower concentration of glucose and glycine in lung tissue, accompanied by increased levels of glucose, lactate, acetate, 3-hydroxybutyrate, and creatine in bronchoalveolar lavage fluid. In serum, increased levels of phosphatidylcholine, oleamide, sphinganine, hexadecenal and lysine, and decreased levels of lyso-phosphatidylcholine and sphingosine were identified by MS. Conclusions: This pilot study suggests that VILI is characterized by a particular metabolic profile that can be identified by MRS and MS. The metabolic profile, though preliminary and pending confirmation in larger data sets, suggests alterations in energy and membrane lipids. SUPPLEMENTAL DIGITAL CONTENT IS AVAILABLE IN THE TEXT

scholarly journals Impact of acute exposure to cigarette smoke on airway gene expression

2018 ◽  
Vol 50 (9) ◽  
pp. 705-713 ◽  
Author(s):  
E. Billatos ◽  
A. Faiz ◽  
Y. Gesthalter ◽  
A. LeClerc ◽  
Y. O. Alekseyev ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Lung Cancer ◽  
Cigarette Smoke ◽  
Smoke Exposure ◽  
Acute Exposure ◽  
Cigarette Smoke Exposure ◽  
Airway Epithelial ◽  
Long Term Effects ◽  
Chronic Smoking

Background: Understanding effects of acute smoke exposure (ASE) on airway epithelial gene expression and their relationship with the effects of chronic smoke exposure may provide biological insights into the development of smoking-related respiratory diseases. Methods: Bronchial airway epithelial cell brushings were collected from 63 individuals without recent cigarette smoke exposure and before and 24 h after smoking three cigarettes. RNA from these samples was profiled on Affymetrix Human Gene 1.0 ST microarrays. Results: We identified 91 genes differentially expressed 24 h after ASE (false discovery rate < 0.25). ASE induced genes involved in xenobiotic metabolism, oxidative stress, and inflammation and repressed genes related to cilium morphogenesis and cell cycle. While many genes altered by ASE are altered similarly in chronic smokers, metallothionein genes are induced by ASE and suppressed in chronic smokers. Metallothioneins are also suppressed in current and former smokers with lung cancer relative to those without lung cancer. Conclusions: Acute exposure to as little as three cigarettes and chronic smoking induce largely concordant changes in airway epithelial gene expression. Differences in short-term and long-term effects of smoking on metallothionein expression and their relationship to lung cancer requires further study given these enzymes’ role in the oxidative stress response.

Biomarkers for oxidative stress in acute lung injury induced in rabbits submitted to different strategies of mechanical ventilation

2012 ◽  
Vol 112 (7) ◽  
pp. 1184-1190 ◽  
Author(s):  
Carlos Fernando Ronchi ◽  
Jose Roberto Fioretto ◽  
Ana Lucia Anjos Ferreira ◽  
Carolina Bragiola Berchieri-Ronchi ◽  
Camila Renata Correa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mechanical Ventilation ◽  
Dna Damage ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Comet Assay ◽  
Lung Tissue ◽  
Significant Positive Correlation ◽  
Target Tissue ◽  
Total Antioxidant

Oxidative damage has been said to play an important role in pulmonary injury, which is associated with the development and progression of acute respiratory distress syndrome (ARDS). We aimed to identify biomarkers to determine the oxidative stress in an animal model of acute lung injury (ALI) using two different strategies of mechanical ventilation. Rabbits were ventilated using either conventional mechanical ventilation (CMV) or high-frequency oscillatory ventilation (HFOV). Lung injury was induced by tracheal saline infusion (30 ml/kg, 38°C). In addition, five healthy rabbits were studied for oxidative stress. Isolated lymphocytes from peripheral blood and lung tissue samples were analyzed by alkaline single cell gel electrophoresis (comet assay) to determine DNA damage. Total antioxidant performance (TAP) assay was applied to measure overall antioxidant performance in plasma and lung tissue. HFOV rabbits had similar results to healthy animals, showing significantly higher antioxidant performance and lower DNA damage compared with CMV in lung tissue and plasma. Total antioxidant performance showed a significant positive correlation ( r = 0.58; P = 0.0006) in plasma and lung tissue. In addition, comet assay presented a significant positive correlation ( r = 0.66; P = 0.007) between cells recovered from target tissue and peripheral blood. Moreover, antioxidant performance was significantly and negatively correlated with DNA damage ( r = −0.50; P = 0.002) in lung tissue. This study indicates that both TAP and comet assay identify increased oxidative stress in CMV rabbits compared with HFOV. Antioxidant performance analyzed by TAP and oxidative DNA damage by comet assay, both in plasma, reflects oxidative stress in the target tissue, which warrants further studies in humans.

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