β-Naphthoflavone treatment attenuates neonatal hyperoxic lung injury in wild type and Cyp1a2-knockout mice

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.

Download Full-text

Resistance of hypotransferrinemic mice to hyperoxia-induced lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.277.6.l1214 ◽

1999 ◽

Vol 277 (6) ◽

pp. L1214-L1223 ◽

Cited By ~ 6

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.

Download Full-text

Susceptibility to ozone-induced acute lung injury in iNOS-deficient mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00297.2001 ◽

2002 ◽

Vol 282 (3) ◽

pp. L540-L545 ◽

Cited By ~ 37

Author(s):

Nicholas J. Kenyon ◽

Albert van der Vliet ◽

Bettina C. Schock ◽

Tatsuya Okamoto ◽

Gabrielle M. McGrew ◽

...

Keyword(s):

Nitric Oxide ◽

Lung Injury ◽

Knockout Mice ◽

Lung Damage ◽

Ozone Exposure ◽

Wild Type ◽

Cell Content ◽

Inflammatory Protein ◽

Inos Knockout Mice ◽

Oxide Synthase

Mice deficient in inducible nitric oxide synthase (iNOS; C57Bl/6Ai-[KO] NOS2 N5) or wild-type C57Bl/6 mice were exposed to 1 part/million of ozone 8 h/night or to filtered air for three consecutive nights. Endpoints measured included lavagable total protein, macrophage inflammatory protein (MIP)-2, matrix metalloproteinase (MMP)-9, cell content, and tyrosine nitration of whole lung proteins. Ozone exposure caused acute edema and an inflammatory response in the lungs of wild-type mice, as indicated by significant increases in lavage protein content, MIP-2 and MMP-9 content, and polymorphonuclear leukocytes. The iNOS knockout mice showed significantly greater levels of lung injury by all of these criteria than did the wild-type mice. We conclude that iNOS knockout mice are more susceptible to acute lung damage induced by exposure to ozone than are wild-type C57Bl/6 mice and that protein nitration is associated with the degree of inflammation and not dependent on iNOS-derived nitric oxide.

Download Full-text

Leukocyte-derived extracellular superoxide dismutase does not contribute to airspace EC-SOD after interstitial pulmonary injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00360.2010 ◽

2012 ◽

Vol 302 (1) ◽

pp. L160-L166 ◽

Cited By ~ 4

Author(s):

Michelle L. Manni ◽

Michael W. Epperly ◽

Wei Han ◽

Timothy S. Blackwell ◽

Steven R. Duncan ◽

...

Keyword(s):

Bone Marrow ◽

Superoxide Dismutase ◽

Lung Injury ◽

Knockout Mice ◽

Inflammatory Diseases ◽

Early Stage ◽

Lavage Fluid ◽

Extracellular Superoxide Dismutase ◽

Wild Type ◽

Lung Injury Model

The antioxidant enzyme extracellular superoxide dismutase (EC-SOD) is abundant in the lung and is known to limit inflammation and fibrosis following numerous pulmonary insults. Previous studies have reported a loss of full-length EC-SOD from the pulmonary parenchyma with accumulation of proteolyzed EC-SOD in the airspace after an interstitial lung injury. However, following airspace only inflammation, EC-SOD accumulates in the airspace without a loss from the interstitium, suggesting this antioxidant may be released from an extrapulmonary source. Because leukocytes are known to express EC-SOD and are prevalent in the bronchoalveolar lavage fluid (BALF) after injury, it was hypothesized that these cells may transport and release EC-SOD into airspaces. To test this hypothesis, C57BL/6 wild-type and EC-SOD knockout mice were irradiated and transplanted with bone marrow from either wild-type mice or EC-SOD knockout mice. Bone marrow chimeric mice were then intratracheally treated with asbestos and killed 3 and 7 days later. At both 3 and 7 days following asbestos injury, mice without pulmonary EC-SOD expression but with EC-SOD in infiltrating and resident leukocytes did not have detectable levels of EC-SOD in the airspaces. In addition, leukocyte-derived EC-SOD did not significantly lessen inflammation or early stage fibrosis that resulted from asbestos injury in the lungs. Although it is not influential in the asbestos-induced interstitial lung injury model, EC-SOD is still known to be present in leukocytes and may play an influential role in attenuating pneumonias and other inflammatory diseases.

Download Full-text

Serum amyloid A3 confers protection against acute lung injury in Pseudomonas aeruginosa-infected mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00309.2019 ◽

2020 ◽

Vol 318 (2) ◽

pp. L314-L322 ◽

Cited By ~ 3

Author(s):

Yu Fan ◽

Gufang Zhang ◽

Chi Teng Vong ◽

Richard D. Ye

Keyword(s):

Pseudomonas Aeruginosa ◽

Acute Lung Injury ◽

Lung Injury ◽

Knockout Mice ◽

Superoxide Anion ◽

Inflammatory Responses ◽

Serum Amyloid ◽

Wild Type ◽

Superoxide Anion Production ◽

Anion Production

Pseudomonas aeruginosa is a gram-negative bacterium associated with serious illnesses, including ventilator-associated pneumonia and various sepsis syndromes in humans. Understanding the host immune mechanisms against P. aeruginosa is, therefore, of clinical importance. The present study identified serum amyloid A3 (SAA3) as being highly inducible in mouse bronchial epithelium following P. aeruginosa infection. Genetic deletion of Saa3 rendered mice more susceptible to P. aeruginosa infection with decreased neutrophil superoxide anion production, and ex vivo treatment of mouse neutrophils with recombinant SAA3 restored the ability of neutrophils to produce superoxide anions. The SAA3-deficient mice showed exacerbated inflammatory responses, which was characterized by pronounced neutrophil infiltration, elevated expression of TNF-α, KC/CXCL1, and MIP-2/CXCL2 in bronchoalveolar lavage fluid (BALF), and increased lung microvascular permeability compared with their wild-type littermates. BALF neutrophils from Saa3 knockout mice exhibited reduced superoxide anion production compared with neutrophils from wild-type mice. Adoptive transfer of SAA3-treated neutrophils to Saa3 knockout mice ameliorated P. aeruginosa-induced acute lung injury. These findings demonstrate that SAA3 not only serves as a biomarker for infection and inflammation, but also plays a protective role against P. aeruginosa infection-induced lung injury in part through augmentation of neutrophil bactericidal functions.

Download Full-text

Mice Lacking the Cytochrome P450 1B1 Gene Are Less Susceptible to Hyperoxic Lung Injury Than Wild Type

Toxicological Sciences ◽

10.1093/toxsci/kfy154 ◽

2018 ◽

Vol 165 (2) ◽

pp. 462-474 ◽

Cited By ~ 6

Author(s):

Alex C Veith ◽

Boura’a Bou Aram ◽

Weiwu Jiang ◽

Lihua Wang ◽

Guodong Zhou ◽

...

Keyword(s):

Cytochrome P450 ◽

Lung Injury ◽

Wild Type ◽

Cytochrome P450 1B1 ◽

Hyperoxic Lung Injury

Download Full-text

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.90509.2008 ◽

2009 ◽

Vol 297 (4) ◽

pp. L687-L697 ◽

Cited By ~ 11

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.

Download Full-text

Differential roles of p55 and p75 tumor necrosis factor receptors on stretch-induced pulmonary edema in mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00284.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. L60-L68 ◽

Cited By ~ 46

Author(s):

Michael R. Wilson ◽

Michael E. Goddard ◽

Kieran P. O'Dea ◽

Sharmila Choudhury ◽

Masao Takata

Keyword(s):

Tumor Necrosis Factor ◽

Lung Injury ◽

Pulmonary Edema ◽

Knockout Mice ◽

Tumor Necrosis ◽

Tnf Receptor ◽

Wild Type ◽

Double Knockout ◽

Edema Formation ◽

Necrosis Factor

Ventilator-induced lung injury plays a crucial role in the outcome of patients with acute lung injury. Previous studies have shown a role for the cytokine tumor necrosis factor-α (TNF) in stretch-induced alveolar neutrophil recruitment, but the involvement of TNF in stretch-induced pulmonary edema is unclear. We investigated the effects of TNF through its individual p55 and p75 receptors on early pulmonary edema formation during high stretch ventilation, before neutrophil infiltration. Anesthetized wild-type or TNF receptor single/double knockout mice were ventilated with high tidal volume (∼38 ml/kg) for 2 h or until they developed arterial hypotension. Pulmonary edema was assessed by physiological parameters including respiratory mechanics and blood gases, and by lavage fluid protein, lung wet:dry weight ratio, and lung permeability measurements using fluorescence-labeled albumin. High stretch ventilation in wild-type and TNF receptor double knockout animals induced similar pulmonary edema, and only 25–30% of mice completed the protocol. In contrast, the p55 receptor knockout mice were strongly protected from edema formation, with all animals completing the protocol. Myeloperoxidase assay indicated that this protective effect was not associated with decreased pulmonary neutrophil sequestration. The p75 receptor knockout mice, however, displayed increased susceptibility to edema formation, and no animals survived the full 2 h. These results demonstrate a novel role for TNF signaling (independent from its effects on neutrophil recruitment) specifically through the p55 receptor, in promoting high stretch-induced pulmonary edema, whereas p75 signaling may play an opposing role.

Download Full-text