Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxygen supplementation is used as therapy to support critically ill patients with severe respiratory impairment. Although hyperoxia has been shown to enhance the lung susceptibility to subsequent bacterial infection, the mechanisms underlying enhanced susceptibility remain enigmatic. We have reported that disruption of NF-E2-related factor 2 (Nrf2), a master transcription regulator of various stress response pathways, enhances susceptibility to hyperoxia-induced acute lung injury in mice, and have also demonstrated an association between a polymorphism in the NRF2 promoter and increased susceptibility to acute lung injury. In this study, we show that Nrf2-deficient (Nrf2(-/-)) but not wild-type (Nrf2(+/+)) mice exposed to sublethal hyperoxia succumbed to death during recovery after Pseudomonas aeruginosa infection. Nrf2-deficiency caused persistent bacterial pulmonary burden and enhanced levels of inflammatory cell infiltration as well as edema. Alveolar macrophages isolated from Nrf2(-/-) mice exposed to hyperoxia displayed persistent oxidative stress and inflammatory cytokine expression concomitant with diminished levels of antioxidant enzymes, such as Gclc, required for glutathione biosynthesis. In vitro exposure of Nrf2(-/-) macrophages to hyperoxia strongly diminished their antibacterial activity and enhanced inflammatory cytokine expression compared with Nrf2(+/+) cells. However, glutathione supplementation during hyperoxic insult restored the ability of Nrf2(-/-) cells to mount antibacterial response and suppressed cytokine expression. Thus, loss of Nrf2 impairs lung innate immunity and promotes susceptibility to bacterial infection after hyperoxia exposure, ultimately leading to death of the host.
 ...
PMID:Innate immunity against bacterial infection following hyperoxia exposure is impaired in NRF2-deficient mice. 1973 19

In the initial stage of retinopathy of prematurity (ROP), hyperoxia causes retinal blood vessel obliteration. This is thought to occur in part through oxidative stress-induced apoptosis of endothelial cells. This study was designed to determine what role NF-E2-related factor 2 (Nrf2) plays in this process. Nrf2 is a transcription factor of the anti-oxidant response element that, if induced, may protect the retina from hyperoxia-induced oxidative stress. Nrf2 knockout mice (Nrf2-/-), Nrf2 wild type control mice (Nrf2+/+), and C57BL/6 mice were exposed to hyperoxia (75% O(2)) or normoxia from P7 through P12. Mice were sacrificed on P9 and P12 and the retinas were stained with GSA lectin-Cy3 to visualize retinal blood vessels. Hyperoxia exposed retinas were flat mounted and photographed, then the size of the avascular areas was determined. Additionally, retinas were cryopreserved after lectin staining and area analysis and then sectioned. Secondary or deep capillaries were then hand-counted in sections. In hyperoxia-treated mice, the avascular areas in Nrf2-/- P9 mice were significantly larger than those in Nrf2+/+ P9 mice (P = 0.01). However, there was no significant difference between Nrf2-/- and Nrf2+/+ mice at P12. Avascular areas at P12 were significantly smaller than that at P9 in Nrf2-/-, Nrf2+/+, and C57BL/6 mice (P = 0.0011, P = 0.009, and P = 0.001 respectively). The numbers of deep or secondary capillaries in air-reared Nrf2-/- mice were significantly decreased, when compared to Nrf2+/+ mice at P9 (P = 0.0082). On the other hand, there was no significant difference in deep capillary formation between air-reared Nrf2-/- and Nrf2+/+ mice at P12. Akt signaling activates Nrf2 and Akt was localized to retinal blood vessels in all animals and was increased in Nrf2+/+ and Nrf2-/- mice exposed to hyperoxia as compared to normoxia mice. Interestingly, during normal development this protection by Nrf2 occurs in a specific window of time that is also shared by angiogenesis. Hyperoxia treatment revealed a similar window of time where Nrf2 regulated anti-oxidant production was beneficial and contributed to the endothelial survival.
 ...
PMID:Role of Nrf2 in retinal vascular development and the vaso-obliterative phase of oxygen-induced retinopathy. 2006 9

Lung epithelial and endothelial cell death caused by pro-oxidant insults is a cardinal feature of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) patients. The NF-E2-related factor 2 (NRF2) activation in response to oxidant exposure is crucial to the induction of several antioxidative and cytoprotective enzymes that mitigate cellular stress. Since prolonged exposure to hyperoxia causes cell death, we hypothesized that chronic hyperoxia impairs NRF2 activation, resulting in cell death. To test this hypothesis, we exposed nonmalignant small airway epithelial cells (AECs) to acute (1-12 h) and chronic (36-48 h) hyperoxia and evaluated cell death, NRF2 nuclear accumulation and target gene expression, and NRF2 recruitment to the endogenous HMOX1 and NQO1 promoters. As expected, hyperoxia gradually induced death in AECs, noticeably and significantly by 36 h; ~60% of cells were dead by 48 h. However, we unexpectedly found increased expression levels of NRF2-regulated antioxidative genes and nuclear NRF2 in AECs exposed to chronic hyperoxia as compared to acute hyperoxia. Chromatin Immunoprecipitation (ChIP) assays revealed an increased recruitment of NRF2 to the endogenous HMOX1 and NQO1 promoters in AECs exposed to acute or chronic hyperoxia. Thus, our findings demonstrate that NRF2 activation and antioxidant gene expression are functional during hyperoxia-induced lung epithelial cell death and that chronic hyperoxia does not impair NRF2 signaling overall.
 ...
PMID:The NRF2 activation and antioxidative response are not impaired overall during hyperoxia-induced lung epithelial cell death. 2373 42

The aim of the study was to investigate the effects of substance P (SP) in hyperoxia-induced lung injury in newborn rats. Thirty-two rat pups were randomly divided into four groups: normoxia/saline, normoxia/SP, hyperoxia/saline and hyperoxia/SP. In a separate set of experiments, the neonatal rat pups were exposed to 21% or >95% O2 for 14 days with or without intraperitoneal administration of SP. On day 14, the animals were sacrificed and the lungs were processed for histology and biochemical analysis. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was used for the detection of apoptosis. Antioxidant capacity was assessed by glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD), oxidative stress was assessed by determining the extent of formation of malondialdehyde (MDA), activities of NADPH oxidase activity, and formation of reactive oxygen species (ROS). The activity of phospho-p38 (p-p38) and -ERK1/2 (p-ERK1/2) proteins and expression of NF-E2-related factor 2 (NRF2) were detected by Western blot, and the expression of p-p38 was detected by immunofluorescence analysis. Compared with the hyperoxia treatment, the lung damage was significantly ameliorated following the SP treatment. Furthermore, the lungs from the pups exposed to hyperoxia TUNEL-positive nuclei increased markedly and decreased significantly after SP treatment. The levels of MDA decreased and that of GSH-Px and SOD increased following the SP treatment. The SP treatment significantly suppressed the activity of NADPH oxidase and reduced ROS production. SP stimulation may result in blocking p38 MAPK and ERK signaling pathways, and the activities of p-p38 and p-ERK, and expression of NRF2 decreased following the SP treatment. These findings indicate that SP can ameliorate hyperoxic lung injury through decreasing cell apoptosis, elevating antioxidant activities, and attenuating oxidative stress.
 ...
PMID:Substance P protects against hyperoxic-induced lung injury in neonatal rats. 2527 19

BACKGROUND We have explored sex differences in ability to maintain redox balance during acute oxidative stress in brains of mice. We aimed to determine if there were differences in oxidative/antioxidative status upon hyperoxia in brains of reproductively senescent CBA/H mice in order to elucidate some of the possible mechanisms of lifespan regulation. MATERIAL AND METHODS The brains of 12-month-old male and female CBA/H mice (n=9 per sex and treatment) subjected to 18-h hyperoxia were evaluated for lipid peroxidation (LPO), antioxidative enzyme expression and activity - superoxide dismutase 1 and 2 (Sod-1, Sod-2), catalase (Cat), glutathione peroxidase 1 (Gpx-1), heme-oxygenase 1 (Ho-1), nad NF-E2-related factor 2 (Nrf2), and for 2-deoxy-2-[18F] fluoro-D-glucose (18FDG) uptake. RESULTS No increase in LPO was observed after hyperoxia, regardless of sex. Expression of Nrf-2 showed significant downregulation in hyperoxia-treated males (p=0.001), and upregulation in hyperoxia-treated females (p=0.023). Also, in females hyperoxia upregulated Sod-1 (p=0.046), and Ho-1 (p=0.014) genes. SOD1 protein was upregulated in both sexes after hyperoxia (p=0.009 for males and p=0.011 for females). SOD2 protein was upregulated only in females (p=0.008) while CAT (p=0.026) and HO-1 (p=0.042) proteins were increased after hyperoxia only in males. Uptake of 18FDG was decreased after hyperoxia in the back brain of females. CONCLUSIONS We found that females at their reproductive senescence are more susceptible to hyperoxia, compared to males. We propose this model of hyperoxia as a useful tool to assess sex differences in adaptive response to acute stress conditions, which may be partially responsible for observed sex differences in longevity of CBA/H mice.
 ...
PMID:Diminished Resistance to Hyperoxia in Brains of Reproductively Senescent Female CBA/H Mice. 2637 31