Male sex is considered an independent predictor for the development of bronchopulmonary dysplasia (BPD) after adjusting for other confounders. BPD is characterized by an arrest in lung development ...with marked impairment of alveolar septation and vascular development. The reasons underlying sexually dimorphic outcomes in premature neonates are not known. In this investigation, we tested the hypothesis that male neonatal mice will be more susceptible to hyperoxic lung injury and will display larger arrest in lung alveolarization. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia 95% FiO2, postnatal day (PND) 1-5 and euthanized on PND 7 and 21. Extent of alveolarization, pulmonary vascularization, inflammation, and modulation of the NF-κB pathway were determined and compared with room air controls. Macrophage and neutrophil infiltration was significantly increased in hyperoxia-exposed animals but was increased to a larger extent in males compared with females. Lung morphometry showed a higher mean linear intercept (MLI) and a lower radial alveolar count (RAC) and therefore greater arrest in lung development in male mice. This was accompanied by a significant decrease in the expression of markers of angiogenesis (PECAM1 and VEGFR2) in males after hyperoxia exposure compared with females. Interestingly, female mice showed increased activation of the NF-κB pathway in the lungs compared with males. These results support the hypothesis that sex plays a crucial role in hyperoxia-mediated lung injury in this model. Elucidation of the sex-specific molecular mechanisms may aid in the development of novel individualized therapies to prevent/treat BPD.
NF-κB in oxidative stress Lingappan, Krithika
Current opinion in toxicology,
02/2018, Volume:
7
Journal Article
Peer reviewed
Open access
The transcription factor nuclear factor-κB (NF-κB) modulates gene expression in diverse cellular processes such as innate immune response, embryogenesis and organ development, cell proliferation and ...apoptosis, and stress responses to a variety of noxious stimuli. When cellular production of reactive oxygen species (ROS) overwhelms its antioxidant capacity, it leads to a state of oxidative stress, which in turn contributes to the pathogenesis of several human diseases. Different models of oxidative stress have been studied to elucidate the effects of oxidant stress on NF-κB related activities. ROS can both activate and repress NF-κB signaling in a phase and context dependent manner. The NF-κB pathway can have both anti- and pro-oxidant roles in the setting of oxidative stress. In this review, we focus on role of oxidative stress on different mediators of the NF-κB pathway, and the role of NF-κB activation in the modulation of oxidative stress. A greater understanding of the complex interplay between the NF-κB signaling and oxidative stress may lead to the development of therapeutic strategies for the treatment of a myriad of human diseases for which oxidative stress has an etiologic role.
•Modulation of the NF-κB pathway by oxidative stress is cell type and context specific.•Reactive oxygen species have bidirectional effects on NF-KB signaling depending on the duration and context of exposure.•Activation of NF-κB pathway can have both anti- and pro-oxidant effects.
The study examines the whole blood transcriptome profile before and after cardiopulmonary bypass (CPB) in neonates with hypoplastic left heart syndrome (HLHS), a severe form of congenital heart ...disease, that can develop low cardiac output syndrome (LCOS). Whole blood mRNA transcriptome profiles of 13 neonates with HLHS before and after their first palliative surgery were analyzed to determine differentially expressed genes and pathways. The median age and weight at surgery were 4 days and 3.2 kg, respectively. Of the 13 patients, 8 developed LCOS. There was no significant difference between CPB, aortic cross clamp, deep hypothermic cardiac arrest times between patients that develop LCOS and those that do not. Upon comparing differential gene expression profiles between patients that develop LCOS and those that do not in pre-operative samples, 1 gene was up-regulated and 13 were down regulated. In the post-operative samples, 4 genes were up-regulated, and 4 genes were down regulated when patients that develop LCOS were compared to those that do not. When comparing post-operative samples to pre-operative samples in the patients that do not develop LCOS, 1484 genes were up-regulated, and 1388 genes were down regulated; while patients that developed LCOS had 2423 up-regulated genes, and 2414 down regulated genes for the same pre to post-operative comparison. Pathway analysis revealed differential regulation of inflammatory pathways (IL signaling, PDGF, NOTCH1, NGF, GPCR) and metabolic pathways (heme metabolism, oxidative phosphorylation, protein metabolism including amino acid and derivatives, fatty acid metabolism, TCA cycle and respiratory electron transport chain). By identifying altered transcriptome profiles related to inflammation and metabolism in neonates with HLHS who develop LCOS after CPB, this study opens for exploration novel pathways and potential therapeutic targets to improve outcomes in this high-risk population.
Premature male neonates are at a greater risk of developing bronchopulmonary dysplasia (BPD). The reasons underlying sexually dimorphic outcomes in premature neonates are not known. The role of ...miRNAs in mediating sex biases in BPD is understudied. Analysis of the pulmonary transcriptome revealed that a large percentage of angiogenesis-related differentially expressed genes are miR-30a targets. We tested the hypothesis that there is differential expression of miR-30a in vivo and in vitro in neonatal human pulmonary microvascular endothelial cells (HPMECs) upon exposure to hyperoxia. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia 95% fraction of inspired oxygen (Fi
), postnatal day ( PND) 1-5 and euthanized on PND 7 and 21. HPMECs (18-24-wk gestation donors) were subjected to hyperoxia (95% O
and 5% CO
) or normoxia (air and 5% CO
) up to 72 h. miR-30a expression was increased in both males and females in the acute phase ( PND 7) after hyperoxia exposure. However, at PND 21 (recovery phase), female mice showed significantly higher miR-30a expression in the lungs compared with male mice. Female HPMECs showed greater expression of miR-30a in vitro upon exposure to hyperoxia. Delta-like ligand 4 (Dll4) was an miR-30a target in HPMECs and showed sex-specific differential expression. miR-30a increased angiogenic sprouting in vitro in female HPMECs. Lastly, we show decreased expression of miR-30a and increased expression of DLL4 in human BPD lung samples compared with controls. These results support the hypothesis that miR-30a could, in part, contribute to the sex-specific molecular mechanisms in play that lead to the sexual dimorphism in BPD.
•Caffeine at 0.05mM decreases oxidative stress in hyperoxia.•Caffeine at 1mM decreases cell viability, increases oxidative stress in hyperoxia.•Caffeine at 1 but not 0.05mM, abrogates ...hyperoxia-induced G2/M arrest.
Caffeine is used to prevent bronchopulmonary dysplasia (BPD) in premature neonates. Hyperoxia contributes to the development of BPD, inhibits cell proliferation and decreases cell survival. The mechanisms responsible for the protective effect of caffeine in pulmonary oxygen toxicity remain largely unknown. A549 and MLE 12 pulmonary epithelial cells were exposed to hyperoxia or maintained in room air, in the presence of different concentrations (0, 0.05, 0.1 and 1mM) of caffeine. Caffeine had a differential concentration-specific effect on cell cycle progression, oxidative stress and viability, with 1mM concentration being deleterious and 0.05mM being protective. Reactive oxygen species (ROS) generation during hyperoxia was modulated by caffeine in a similar concentration-specific manner. Caffeine at 1mM, but not at the 0.05mM concentration decreased the G2 arrest in these cells. Taken together this study shows the novel funding that caffeine has a concentration-specific effect on cell cycle regulation, ROS generation, and cell survival in hyperoxic conditions.
Cytochrome P4501A (CYP1A) enzymes play important roles in xenobiotic and endobiotic metabolism. Owing to uncoupling reactions during the enzymatic cycle, CYP1A enzymes can release reactive oxygen ...species (ROS) in the form of superoxide radical, hydrogen peroxide, hydroxyl radical, etc. An imbalance between production of free radicals and the ability of antioxidants to detoxify the free radicals can lead to accumulation of ROS, which in turn can lead to oxidative stress. Oxidative stress can lead to inflammation and toxicity, which in turn can cause human diseases such as bronchopulmonary disease, acute respiratory distress syndrome, renal hypertension, etc. CYP1A enzymes, depending on the organ system, they either contribute or protect against oxidative injury. Thus, they have dual roles in regard to oxidative stress. This review presents an overview of the mechanistic relationship between CYP1A enzymes and oxidative stress in relation to various diseases in different organs (e.g. liver, lungs, heart, kidneys, and reproductive organs).
Recovery from lung injury during the neonatal period requires the orchestration of many biological pathways. The modulation of such pathways can drive the developing lung towards proper repair or ...persistent maldevelopment that can lead to a disease phenotype. Sex as a biological variable can regulate these pathways differently in the male and female lung exposed to neonatal hyperoxia. In this study, we assessed the contribution of cellular diversity in the male and female neonatal lung following injury. Our objective was to investigate sex and cell-type specific transcriptional changes that drive repair or persistent injury in the neonatal lung and delineate the alterations in the immune-endothelial cell communication networks using single cell RNA sequencing (sc-RNAseq) in a murine model of hyperoxic injury. We generated transcriptional profiles of >55,000 cells isolated from the lungs of postnatal day 1 (PND 1; pre-exposure), PND 7, and PND 21neonatal male and female C57BL/6 mice exposed to 95 % FiO
between PND 1-5 (saccular stage of lung development). We show the presence of sex-based differences in the transcriptional states of lung endothelial and immune cells at PND 1 and PND 21. Furthermore, we demonstrate that biological sex significantly influences the response to injury, with a greater number of differentially expressed genes showing sex-specific patterns than those shared between male and female lungs. Pseudotime trajectory analysis highlighted genes needed for lung development that were altered by hyperoxia. Finally, we show intercellular communication between endothelial and immune cells at saccular and alveolar stages of lung development with sex-based biases in the crosstalk and identify novel ligand-receptor pairs. Our findings provide valuable insights into the cell diversity, transcriptional state, developmental trajectory, and cell-cell communication underlying neonatal lung injury, with implications for understanding lung development and possible therapeutic interventions while highlighting the crucial role of sex as a biological variable.
The lung macrophages play a crucial role in health and disease. Sexual dimorphism significantly impacts the phenotype and function of tissue-resident macrophages. The primary mechanisms responsible ...for sexually dimorphic outcomes in bronchopulmonary dysplasia (BPD) remain unidentified. We tested the hypothesis that biological sex plays a crucial role in the transcriptional state of alveolar macrophages, using neonatal murine hyperoxia-induced lung injury as a relevant model for human BPD. The effects of neonatal hyperoxia exposure (95 % FiO2, PND1-5: saccular stage) on the lung myeloid cells acutely after injury and during normoxic recovery were measured. Alveolar macrophages (AM) from room air- and hyperoxia exposed from male and female neonatal murine lungs were subjected to bulk-RNA Sequencing. AMs are significantly depleted in the hyperoxia-exposed lung acutely after injury, with subsequent recovery in both sexes. The transcriptome of the alveolar macrophages is impacted by neonatal hyperoxia exposure and by sex as a biological variable. Pathways related to DNA damage and interferon-signaling were positively enriched in female AMs. Metabolic pathways related to glucose and carbohydrate metabolism were positively enriched in the male AMs, while oxidative phosphorylation was negatively enriched. These pathways were shared with monocytes and airway macrophages from intubated male and female human premature neonates.
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•Alveolar macrophages (AM) are depleted after neonatal hyperoxia exposure.•Sex modulates the AM transcriptional state after hyperoxia exposure.•Sex-specific pathways in human neonatal airway myeloid cells with lung injury.
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