scholarly journals Resistance of hypotransferrinemic mice to hyperoxia-induced lung injury

1999 ◽  
Vol 277 (6) ◽  
pp. L1214-L1223 ◽  
Author(s):  
Funmei Yang ◽  
Jacqueline J. Coalson ◽  
Heather H. Bobb ◽  
Jacqueline D. Carter ◽  
Jameela Banu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lung Injury ◽  
Alveolar Macrophages ◽  
Lung Damage ◽  
Mouse Lung ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Chronic Pulmonary Diseases ◽  
Hyperoxic Lung Injury ◽  
Key Participants

Oxidative stress plays a central role in the pathogenesis of acute and chronic pulmonary diseases. Safe sequestration of iron, which participates in the formation of the hydroxyl radical, is crucial in the lung's defense. We used a mouse line defective in the major iron transport protein transferrin to investigate the effect of aberrant iron metabolism on the lung's defense against oxidative injury. The tolerance to hyperoxic lung injury was greater in the hypotransferrinemic than in wild-type mice as documented by histopathology and biochemical indexes for lung damage. There was no increase in the levels of intracellular antioxidants, inflammatory cytokines, and heme oxygenase-1 in the hypotransferrinemic mouse lung compared with those in wild-type mice. However, there were elevated expressions of ferritin and lactoferrin in the lung of hypotransferrinemic mice, especially in the alveolar macrophages. Our results suggest that pulmonary lactoferrin and ferritin protect animals against oxidative stress, most likely via their capacity to sequester iron, and that alveolar macrophages are the key participants in iron detoxification in the lower respiratory tract.

Deficiency in the c-Jun NH2-terminal kinase signaling pathway confers susceptibility to hyperoxic lung injury in mice

2003 ◽  
Vol 285 (1) ◽  
pp. L250-L257 ◽  
Author(s):  
Danielle Morse ◽  
Leo E. Otterbein ◽  
Simon Watkins ◽  
Sean Alber ◽  
Zhihong Zhou ◽  
...  
Keyword(s):  
Leukocyte Count ◽  
Mouse Lung ◽  
Heme Oxygenase 1 ◽  
Myeloperoxidase Activity ◽  
Adaptive Responses ◽  
Wild Type ◽  
Epithelial Cell Apoptosis ◽  
Hyperoxic Lung Injury ◽  
65 H

Hyperoxia generates an oxidative stress in the mouse lung, which activates the major stress-inducible kinase pathways, including c-Jun NH2-terminal kinase (JNK). We examined the effect of Jnk1 gene deletion on in vivo responses to hyperoxia in mice. The survival of Jnk1-/- mice was reduced relative to wild-type mice after exposure to continuous hyperoxia. Jnk1- /- mice displayed higher protein concentration in bronchoalveolar lavage (BAL) fluid and increased expression of heme oxygenase-1, a stress-inducible gene, after 65 h of hyperoxia. Contrary to other markers of injury, the leukocyte count in BAL fluid of Jnk1- /- mice was markedly diminished relative to that of wild-type mice. The decrease in BAL leukocyte count was not associated with any decrease in lung myeloperoxidase activity at baseline or after hyperoxia treatment. Pretreatment with inhaled lipopolysaccharide increased BAL neutrophil content and extended hyperoxia survival time to a similar extent in Jnk1- /- and wild-type mice. Associated with increased mortality, Jnk1- /- mice had increased pulmonary epithelial cell apoptosis after exposure to hyperoxia compared with wild-type mice. These results indicate that JNK pathways participate in adaptive responses to hyperoxia in mice.

scholarly journals Lung-specific induction of heme oxygenase-1 and hyperoxic lung injury

1998 ◽  
Vol 274 (4) ◽  
pp. L582-L590 ◽  
Author(s):  
Jennifer L. Taylor ◽  
Martha Sue Carraway ◽  
Claude A. Piantadosi
Keyword(s):  
Oxidative Stress ◽  
Enzyme Activity ◽  
Lung Injury ◽  
Heme Oxygenase ◽  
Normal Saline ◽  
Dry Weight ◽  
Heme Oxygenase 1 ◽  
Specific Induction ◽  
Hyperoxic Lung Injury ◽  
Tin Protoporphyrin

Heme oxygenase (HO)-1, which catalyzes heme breakdown, is induced by oxidative stress and may protect against oxidative injury. We hypothesized that induction of HO-1 by hemoglobin (Hb) in the lung would protect the rat from pulmonary O2 toxicity. Rats given intratracheal (IT) Hb showed lung-specific induction of HO-1 by 8 h by Western analysis. Rats were then pretreated for 8 h before 60 h of exposure to 100% O2 with either IT normal saline, Hb, or Hb plus the HO-1 inhibitor tin-protoporphyrin (SnPP). Both the Hb+O2 and Hb+O2+ SnPP animals had less lung injury than normal saline controls as indicated by lower pleural fluid volumes and wet-to-dry weight ratios ( P < 0.01). The improvement in injury in the two Hb-treated groups was the same despite a 61% decrease in HO enzyme activity in the Hb+SnPP group after 60 h of O2. In addition, inhibition of HO activity with SnPP alone before O2exposure did not augment the extent of hyperoxic lung injury. These results demonstrate that IT Hb induces lung HO-1 in the rat and protects against hyperoxia; however, the protection is not mediated by increased HO enzyme activity.

Haptoglobin reduces lung injury associated with exposure to blood

2003 ◽  
Vol 284 (2) ◽  
pp. L402-L409 ◽  
Author(s):  
Funmei Yang ◽  
David J. Haile ◽  
Franklin G. Berger ◽  
Damon C. Herbert ◽  
Emily Van Beveren ◽  
...  
Keyword(s):  
Lung Injury ◽  
Transgenic Mice ◽  
Alveolar Macrophages ◽  
Ferritin Level ◽  
Protective Role ◽  
Heme Oxygenase 1 ◽  
Wild Type ◽  
Intracellular Iron ◽  
High Level ◽  
Mouse Lungs

The biological functions of the acute- phase protein haptoglobin (Hp) may be related to its ability to bind hemoglobin (Hb) or to modulate immune response. Hp is expressed at a high level in lung cells, yet its protective role(s) in the lung is not known. With the use of transgenic mice overexpressing Hp in alveolar macrophages, we demonstrated that Hp diminished Hb-induced lung injury when the lung was exposed to whole blood. In transgenic mouse lungs, Hb was more efficiently removed, and the induction of stress- responsive heme oxygenase-1 gene was significantly lower when compared with wild-type mice. At 24 h after blood treatment, the ferritin level that serves as an index for intracellular iron content was also lower in alveolar macrophages in transgenic mice than in wild-type mice. We propose that an Hp-mediated Hb catabolism process exists in alveolar macrophages. This process is likely coupled to an iron mobilization pathway and may be an efficient mechanism to reduce oxidative damage associated with hemolysis.

scholarly journals A paradoxical protective role for the proinflammatory peptide substance P receptor (NK1R) in acute hyperoxic lung injury

2009 ◽  
Vol 297 (4) ◽  
pp. L687-L697 ◽  
Author(s):  
Marwan Dib ◽  
Zsuzsanna Zsengeller ◽  
Alex Mitsialis ◽  
Bao Lu ◽  
Stewart Craig ◽  
...  
Keyword(s):  
Substance P ◽  
Lung Injury ◽  
Lung Epithelial Cells ◽  
Mouse Lung ◽  
Tunel Staining ◽  
Wild Type ◽  
Bioactive Constituents ◽  
Targeted Deletion ◽  
Hyperoxic Lung Injury

The neuropeptide substance P manifests its biological functions through ligation of a G protein-coupled receptor, the NK1R. Mice with targeted deletion of this receptor reveal a preponderance of proinflammatory properties resulting from ligand activation, demonstrating a neurogenic component to multiple forms of inflammation and injury. We hypothesized that NK1R deficiency would afford a similar protection from inflammation associated with hyperoxia. Counter to our expectations, however, NK1R−/− animals suffered significantly worse lung injury compared with wild-type mice following exposure to 90% oxygen. Median survival was shortened to 84 h for NK1R−/− mice from 120 h for wild-type animals. Infiltration of inflammatory cells into the lungs was significantly increased; NK1R−/− animals also exhibited increased pulmonary edema, hemorrhage, and bronchoalveolar lavage fluid protein levels. TdT-mediated dUTP nick end labeling (TUNEL) staining was significantly elevated in NK1R−/− animals following hyperoxia. Furthermore, induction of metallothionein and Na+-K+-ATPase was accelerated in NK1R−/− compared with wild-type mice, consistent with increased oxidative injury and edema. In cultured mouse lung epithelial cells in 95% O2, however, addition of substance P promoted cell death, suggesting the neurogenic component of hyperoxic lung injury is mediated by additional mechanisms in vivo. Release of bioactive constituents including substance P from sensory neurons results from activation of the vanilloid receptor, TRPV1. In mice with targeted deletion of the TRPV1 gene, acute hyperoxic injury is attenuated relative to NK1R−/− animals. Our findings thus reveal a major neurogenic mechanism in acute hyperoxic lung injury and demonstrate concerted actions of sensory neurotransmitters revealing significant protection for NK1R-mediated functions.

scholarly journals Transduced PEP-1-Heme Oxygenase-1 Fusion Protein Attenuates Lung Injury in Septic Shock Rats

2018 ◽  
Vol 2018 ◽  
pp. 1-12
Author(s):  
Xue-Tao Yan ◽  
Xiang-Hu He ◽  
Yan-Lin Wang ◽  
Zong-Ze Zhang ◽  
Jun-Jiao Tang
Keyword(s):  
Oxidative Stress ◽  
Septic Shock ◽  
Lung Injury ◽  
Fusion Protein ◽  
Heme Oxygenase ◽  
Cecal Ligation ◽  
Protective Role ◽  
Lung Damage ◽  
Heme Oxygenase 1 ◽  
Anti Inflammatory

Oxidative stress and inflammation have been identified to play a vital role in the pathogenesis of lung injury induced by septic shock. Heme oxygenase-1 (HO-1), an effective antioxidant and anti-inflammatory and antiapoptotic substance, has been used for the treatment of heart, lung, and liver diseases. Thus, we postulated that administration of exogenous HO-1 protein transduced by cell-penetrating peptide PEP-1 has a protective role against septic shock-induced lung injury. Septic shock produced by cecal ligation and puncture caused severe lung damage, manifested in the increase in the lung wet/dry ratio, oxidative stress, inflammation, and apoptosis. However, these changes were reversed by treatment with the PEP-1-HO-1 fusion protein, whereas lung injury in septic shock rats was alleviated. Furthermore, the septic shock upregulated the expression of Toll-like receptor 4 (TLR4) and transcription factor NF-κB, accompanied by the increase of lung injury. Administration of PEP-1-HO-1 fusion protein reversed septic shock-induced lung injury by downregulating the expression of TLR4 and NF-κB. Our study indicates that treatment with HO-1 protein transduced by PEP-1 confers protection against septic shock-induced lung injury by its antioxidant, anti-inflammatory, and antiapoptotic effects.

Class B Scavenger Receptors BI and BII Protect Against LPS-induced Acute Lung Injury in Mice by Mediating LPS Clearance

2021 ◽  
Author(s):  
Irina N. Baranova ◽  
Alexander V. Bocharov ◽  
Tatyana G. Vishnyakova ◽  
Zhigang Chen ◽  
Anna A. Birukova ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Transgenic Mice ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Protective Role ◽  
Lung Damage ◽  
Wild Type ◽  
Class B ◽  
Anti Inflammatory

Recent studies suggest an anti-inflammatory protective role for class B scavenger receptor BI (SR-BI) in endotoxin-induced inflammation and sepsis. Other data, including ours, provide evidence for an alternative role of SR-BI, facilitating bacterial and endotoxin uptake, and contributing to inflammation and bacterial infection. Enhanced endotoxin susceptibility of SR-BI deficient mice due to their anti-inflammatory glucocorticoid deficiency complicates understanding SR-BI’s role in endotoxemia/sepsis, calling for use of alternative models. In this study, using hSR-BI and hSR-BII transgenic mice, we found that SR-BI and to a lesser extent its splicing variant SR-BII, protects against LPS-induced lung damage. At 20 hours after intratracheal LPS instillation the extent of pulmonary inflammation and vascular leakage was significantly lower in hSR-BI and hSR-BII transgenic mice compared to wild type mice. Higher bronchoalveolar lavage fluid (BALF) inflammatory cell count and protein content as well as lung tissue neutrophil infiltration found in wild type mice was associated with markedly (2-3 times) increased pro-inflammatory cytokine production as compared to transgenic mice following LPS administration. Markedly lower endotoxin levels detected in BALF of transgenic vs. wild type mice along with the significantly increased BODIPY-LPS uptake observed in lungs of hSR-BI and hSR-BII mice 20 hours after the IT LPS injection suggest that hSR-BI and hSR-BII-mediated enhanced LPS clearance in the airways could represent the mechanism of their protective role against LPS-induced acute lung injury.

Dexpanthenol therapy reduces lung damage in a hyperoxic lung injury in neonatal rats

2015 ◽  
pp. 1-7 ◽  
Author(s):  
Ramazan Ozdemir ◽  
Gulsum Demirtas ◽  
Hakan Parlakpinar ◽  
Alaadin Polat ◽  
Kevser Tanbag ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lung Damage ◽  
Neonatal Rats ◽  
Hyperoxic Lung Injury

scholarly journals Murine Neonatal Oxidant Lung Injury: NRF2-Dependent Predisposition to Adulthood Respiratory Viral Infection and Protection by Maternal Antioxidant

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1874
Author(s):  
Hye-Youn Cho ◽  
Laura Miller-DeGraff ◽  
Ligon A. Perrow ◽  
Wesley Gladwell ◽  
Vijayalakshmi Panduri ◽  
...  
Keyword(s):  
Lung Injury ◽  
Perinatal Death ◽  
Pulmonary Inflammation ◽  
Wild Type ◽  
Protection Mechanisms ◽  
Hyperoxic Lung Injury ◽  
Syncytial Virus ◽  
Pulmonary Protection ◽  
Microarray Analyses ◽  
Neonatal Lungs

NRF2 protects against oxidant-associated airway disorders via cytoprotective gene induction. To examine if NRF2 is an important determinant of respiratory syncytial virus (RSV) susceptibility after neonate lung injury, Nrf2-deficient (Nrf2−/−) and wild-type (Nrf2+/+) mice neonatally exposed to hyperoxia were infected with RSV. To investigate the prenatal antioxidant effect on neonatal oxidative lung injury, time-pregnant Nrf2−/−and Nrf2+/+mice were given an oral NRF2 agonist (sulforaphane) on embryonic days 11.5–17.5, and offspring were exposed to hyperoxia. Bronchoalveolar lavage and histopathologic analyses determined lung injury. cDNA microarray analyses were performed on placenta and neonatal lungs. RSV-induced pulmonary inflammation, injury, oxidation, and virus load were heightened in hyperoxia-exposed mice, and injury was more severe in hyperoxia-susceptible Nrf2−/− mice than in Nrf2+/+ mice. Maternal sulforaphane significantly alleviated hyperoxic lung injury in both neonate genotypes with more marked attenuation of severe neutrophilia, edema, oxidation, and alveolarization arrest in Nrf2−/− mice. Prenatal sulforaphane altered different genes with similar defensive functions (e.g., inhibition of cell/perinatal death and inflammation, potentiation of angiogenesis/organ development) in both strains, indicating compensatory transcriptome changes in Nrf2−/− mice. Conclusively, oxidative injury in underdeveloped lungs NRF2-dependently predisposed RSV susceptibility. In utero sulforaphane intervention suggested NRF2-dependent and -independent pulmonary protection mechanisms against early-life oxidant injury.

scholarly journals Endogenous Hydrogen Sulfide Is an Important Factor in Maintaining Arterial Oxygen Saturation

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan Huang ◽  
Gang Wang ◽  
Zhan Zhou ◽  
Zhengshan Tang ◽  
Ningning Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lung Injury ◽  
Arterial Oxygen Saturation ◽  
Arterial Oxygen ◽  
Wall Thickening ◽  
Alveolar Wall ◽  
Leukocyte Infiltration ◽  
Wild Type ◽  
Interstitial Edema ◽  
And Oxidative Stress

The gasotransmitter H2S is involved in various physiological and pathophysiological processes. The aim of this study was to investigate the physiological functions of H2S in the lungs. In the model of mouse with genetic deficiency in a H2S natural synthesis enzyme cystathionine-γ-lyase (CSE), we found that arterial oxygen saturation (SaO2) was decreased compared with wild type mice. Hypoxyprobe test showed that mild hypoxia occurred in the tissues of heart, lungs and kidneys in Cse-/- mice. H2S donor GYY4137 treatment increased SaO2 and ameliorated hypoxia state in cardiac and renal tissues. Further, we revealed that lung blood perfusion and airway responsiveness were not linked to reduced SaO2 level. Lung injury was found in Cse-/- mice as evidenced by alveolar wall thickening, diffuse interstitial edema and leukocyte infiltration in pulmonary tissues. IL-8, IL-1β, and TNF-α levels were markedly increased and oxidative stress levels were also significantly higher with increased levels of the pro-oxidative biomarker, MDA, decreased levels of the anti-oxidative biomarkers, T-AOC and GSH/GSSG, and reduced superoxide dismutase (SOD) activity in lung tissues of Cse-/- mice compared with those of wild type mice. GYY4137 treatment ameliorated lung injury and suppressed inflammatory state and oxidative stress in lung tissues of Cse-/- mice. A decrease in SaO2 was found in normal mice under hypoxia. These mice displayed lung injury as evidenced by alveolar wall thickening, interstitial edema and leukocyte infiltration. Increased levels of inflammatory cytokines and oxidative stress were also found in lung tissues of the mice with hypoxia insult. GYY4137 treatment increased SaO2 and ameliorated lung injury, inflammation and oxidative stress. Our data indicate that endogenous H2S is an important factor in maintaining normal SaO2 by preventing oxidative stress and inflammation in the lungs.

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