scholarly journals Sex-specific differences in neonatal hyperoxic lung injury

2016 ◽  
Vol 311 (2) ◽  
pp. L481-L493 ◽  
Author(s):  
Krithika Lingappan ◽  
Weiwu Jiang ◽  
Lihua Wang ◽  
Bhagavatula Moorthy
Keyword(s):  
Lung Injury ◽  
Lung Development ◽  
Molecular Mechanisms ◽  
Neutrophil Infiltration ◽  
Sexually Dimorphic ◽  
Female Mice ◽  
Hyperoxia Exposure ◽  
Hyperoxic Lung Injury ◽  
Mean Linear Intercept ◽  
Radial Alveolar Count

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.

scholarly journals MicroRNA-30a as a candidate underlying sex-specific differences in neonatal hyperoxic lung injury: implications for BPD

2019 ◽  
Vol 316 (1) ◽  
pp. L144-L156 ◽  
Author(s):  
Yuhao Zhang ◽  
Cristian Coarfa ◽  
Xiaoyu Dong ◽  
Weiwu Jiang ◽  
Brielle Hayward-Piatkovskyi ◽  
...  
Keyword(s):  
Differential Expression ◽  
Molecular Mechanisms ◽  
Recovery Phase ◽  
Sexually Dimorphic ◽  
Female Mice ◽  
Hyperoxia Exposure ◽  
Hyperoxic Lung Injury ◽  
Fraction Of Inspired Oxygen

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 (FiO2), postnatal day ( PND) 1–5] and euthanized on PND 7 and 21. HPMECs (18–24-wk gestation donors) were subjected to hyperoxia (95% O2 and 5% CO2) or normoxia (air and 5% CO2) 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.

scholarly journals Role of HIF-1α-miR30a-Snai1 Axis in Neonatal Hyperoxic Lung Injury

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Yuhao Zhang ◽  
Xiaoyu Dong ◽  
Krithika Lingappan
Keyword(s):  
Lung Injury ◽  
Vascular Development ◽  
Female Mice ◽  
Severe Impairment ◽  
Hyperoxic Lung Injury ◽  
Postnatal Lung Development ◽  
Inhibitor Treatment

Bronchopulmonary dysplasia (BPD) is characterized by a severe impairment in lung alveolarization and vascular development. We have previously shown that pulmonary angiogenesis is preserved in hyperoxia-exposed female mice accompanied by increased miR-30a expression, which is a proangiogenic miRNA. Also, miR-30a expression is decreased in human BPD. HIF-1α plays an essential role in postnatal lung development, especially in recovery from hyperoxic injury. Snai1 activation promotes pathological fibrosis through many mechanisms including Endo-MT, which may in turn adversely impact lung vascular development. Our objective was to test the hypothesis that higher miR-30a expression through HIF-1α decreases Snai1 expression in females and attenuates injury in the developing lung. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia (P1-5, 0.95 FiO2) and euthanized on P21. Neonatal human pulmonary microvascular endothelial cells (HPMECs; 18-24-week gestation donors; 3/group either sex) were subjected to hyperoxia (95% O2 and 5% CO2) or normoxia (air and 5% CO2) up to 72 h. Snai1 expression was measured in HPMECs in vitro and in neonatal mouse lungs in vivo. Also, Snai1 expression was measured in HPMECs after miR-30a mimic and miR-30a inhibitor treatment. To further establish the potential regulation of miR-30a by Hif-1α, miR-30a expression after Hif-1α inhibition was measured in HPMECs. In vivo, Snai1 expression was decreased in neonatal female lungs compared to males at P7. Increased Snai1 expression was seen in male HPMECs upon exposure to hyperoxia in vitro. Treatment with the miR-30a mimic decreased Snai1 expression in HPMECs, while miR-30a inhibition significantly increased Snai1 expression in HPMECs. siRNA-mediated loss of Hif-1α expression in HPMECs decreased miR-30a expression. Hif-1α may lead to differential sex-specific miR-30a expression and may contribute to protection from hyperoxic lung injury in female neonatal mice through decreased Snai1 expression.

Nebulized curcumin protects neonatal lungs from antenatal insult in rats

2021 ◽  
Author(s):  
Cyril Guillier ◽  
Diane Carrière ◽  
Julien Pansiot ◽  
Arielle Maroni ◽  
Elodie Billion ◽  
...  
Keyword(s):  
Lung Development ◽  
Control Diet ◽  
Normal Lung ◽  
Curcumin Treatment ◽  
Rat Pups ◽  
Low Protein ◽  
Morphometric Analyses ◽  
Mean Linear Intercept ◽  
Radial Alveolar Count ◽  
Development Methods

Rationale: Intrauterine growth restriction (IUGR) increases the risk of bronchopulmonary dysplasia (BPD), one of the major complications of prematurity. Antenatal low-protein diet (LPD) exposure in rats induces IUGR and mimics BPD-related alveolarization disorders. Proliferator-activated receptor (PPARg) plays a key role in normal lung development and was found deregulated following LPD exposure. Objectives: Investigate the effects of nebulized curcumin, a natural PPARg agonist, to prevent IUGR-related abnormal lung development. Methods: We studied rat pups antenatally exposed to an LPD or control diet (CTL) and treated with nebulized curcumin (50 mg/kg) or vehicle from postnatal (P) days 1 to 5. The primary readouts were lung morphometric analyses at P21. Immunohistochemistry (P21) and microarrays (P6 and P11) were compared within animals exposed to LPD versus controls, with and without curcumin treatment. Results: Quantitative morphometric analyses revealed that LPD induced abnormal alveolarization as evidenced by a significant increase in Mean Linear Intercept (MLI) observed in P21 LPD-exposed animals. Early curcumin treatment prevented this effect and two-way ANOVA analysis demonstrated significant interaction between diet and curcumin both for MLI (F(1,39)=12.67,p=0.001) and Radial Alveolar Count at P21 (F(1,40)= 6.065, p=0.0182). Immunohistochemistry for FABP4, a major regulator of PPARg pathway showed a decreased FABP4+ alveolar cell density in LPD-exposed animals treated by curcumin. Transcriptomic analysis showed that early curcumin significantly prevented the activation of pro-fibrotic pathways observed at P11 in LPD-exposed animals. Conclusion: Nebulized curcumin appears to be a promising strategy to prevent alveolarization disorders in IUGR rat pups, targeting pathways involved in lung development.

scholarly journals Sexual dimorphism of the pulmonary transcriptome in neonatal hyperoxic lung injury: identification of angiogenesis as a key pathway

2017 ◽  
Vol 313 (6) ◽  
pp. L991-L1005 ◽  
Author(s):  
Cristian Coarfa ◽  
Yuhao Zhang ◽  
Suman Maity ◽  
Dimuthu N. Perera ◽  
Weiwu Jiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Injury ◽  
Mrna Level ◽  
Sexually Dimorphic ◽  
Rna Seq ◽  
Illumina Hiseq ◽  
Data Set ◽  
Vascular Growth ◽  
Hyperoxic Lung Injury ◽  
High Concentrations

Bronchopulmonary dysplasia (BPD) is characterized by impaired alveolar secondary septation and vascular growth. Exposure to high concentrations of oxygen (hyperoxia) contributes to the development of BPD. The male sex is considered an independent risk factor for the development of BPD. The reasons underlying sexually dimorphic outcomes in premature neonates are not known. We hypothesized that sex-specific modulation of biological processes in the lung under hyperoxic conditions contributes to sex-based differences. Neonatal male and female mice (C57BL/6) were exposed to hyperoxia [95% [Formula: see text], postnatal day (PND) 1–5: saccular stage of lung development] and euthanized on PND 7 or 21. Pulmonary gene expression was studied using RNA-Seq on the Illumina HiSeq 2500 platform. Analysis of the pulmonary transcriptome revealed differential sex-specific modulation of crucial pathways such as angiogenesis, response to hypoxia, inflammatory response, and p53 pathway. Candidate genes from these pathways were validated at the mRNA level by qPCR. Analysis also revealed sex-specific differences in the modulation of crucial transcription factors. Focusing on the differential modulation of the angiogenesis pathway, we also showed sex-specific differential activation of Hif-1α-regulated genes using ChIP-qPCR and differences in expression of crucial genes ( Vegf, VegfR2, and Phd2) modulating angiogenesis. We demonstrate the translational relevance of our findings by showing that our murine sex-specific differences in gene expression correlate with those from a preexisting human BPD data set. In conclusion, we provide novel molecular insights into differential sex-specific modulation of the pulmonary transcriptome in neonatal hyperoxic lung injury and highlight angiogenesis as one of the crucial differentially modulated pathways.

scholarly journals Xuebijing Ameliorates Sepsis-Induced Lung Injury by Downregulating HMGB1 and RAGE Expressions in Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Qiao Wang ◽  
Xin Wu ◽  
Xiaowen Tong ◽  
Zhiling Zhang ◽  
Bing Xu ◽  
...  
Keyword(s):  
Lung Injury ◽  
Molecular Mechanisms ◽  
Weight Ratio ◽  
High Mobility ◽  
Dry Weight ◽  
Neutrophil Infiltration ◽  
Beneficial Effects ◽  
Glycation End Products ◽  
Underlying Mechanisms ◽  
Caecal Ligation And Puncture

Xuebijing (XBJ) injection, a traditional Chinese medicine, has been reported as a promising approach in the treatment of sepsis in China. However, its actual molecular mechanisms in sepsis-induced lung injury are yet unknown. Therefore, this study aimed to investigate the beneficial effects of XBJ on inflammation and the underlying mechanisms in a model of caecal ligation and puncture-(CLP-) induced lung injury. The mice were divided into CLP group, CLP+XBJ group (XBJ, 4 mL/kg per 12 hours), and sham group. The molecular and histological examinations were performed on the lung, serum, and bronchoalveolar lavage (BAL) fluid samples of mice at the points of 6, 24, and 48 hours after CLP. The results show that XBJ reduces morphological destruction and neutrophil infiltration in the alveolar space and lung wet/dry weight ratio, which improves mortality of CLP-induced lung injury. Meanwhile, XBJ treatment downregulates high mobility group box protein 1 (HMGB1) and the receptor for advanced glycation end products (RAGE) expression, as well as neutrophil counts, production of IL-1β, IL-6, and TNF-αin the BAL fluids. In conclusion, these results indicate that XBJ may reduce the mortality through inhibiting proinflammatory cytokines secretion mediated by HMGB1/RAGE axis.

scholarly journals Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo

2013 ◽  
Vol 304 (10) ◽  
pp. L646-L656 ◽  
Author(s):  
Tomohiro Kawamura ◽  
Nobunao Wakabayashi ◽  
Norihisa Shigemura ◽  
Chien-Sheng Huang ◽  
Kosuke Masutani ◽  
...  
Keyword(s):  
Lung Injury ◽  
Molecular Mechanisms ◽  
Gas Analysis ◽  
Hydrogen Gas ◽  
Blood Oxygenation ◽  
Related Factor ◽  
Hydrogen Treatment ◽  
Hyperoxic Lung Injury ◽  
Deficient Mice

Hyperoxic lung injury is a major concern in critically ill patients who receive high concentrations of oxygen to treat lung diseases. Successful abrogation of hyperoxic lung injury would have a huge impact on respiratory and critical care medicine. Hydrogen can be administered as a therapeutic medical gas. We recently demonstrated that inhaled hydrogen reduced transplant-induced lung injury and induced heme oxygenase (HO)-1. To determine whether hydrogen could reduce hyperoxic lung injury and investigate the underlying mechanisms, we randomly assigned rats to four experimental groups and administered the following gas mixtures for 60 h: 98% oxygen (hyperoxia), 2% nitrogen; 98% oxygen (hyperoxia), 2% hydrogen; 98% balanced air (normoxia), 2% nitrogen; and 98% balanced air (normoxia), 2% hydrogen. We examined lung function by blood gas analysis, extent of lung injury, and expression of HO-1. We also investigated the role of NF-E2-related factor (Nrf) 2, which regulates HO-1 expression, by examining the expression of Nrf2-dependent genes and the ability of hydrogen to reduce hyperoxic lung injury in Nrf2-deficient mice. Hydrogen treatment during exposure to hyperoxia significantly improved blood oxygenation, reduced inflammatory events, and induced HO-1 expression. Hydrogen did not mitigate hyperoxic lung injury or induce HO-1 in Nrf2-deficient mice. These findings indicate that hydrogen gas can ameliorate hyperoxic lung injury through induction of Nrf2-dependent genes, such as HO-1. The findings suggest a potentially novel and applicable solution to hyperoxic lung injury and provide new insight into the molecular mechanisms and actions of hydrogen.

scholarly journals Neonatal hyperoxic lung injury favorably alters adult right ventricular remodeling response to chronic hypoxia exposure

2015 ◽  
Vol 308 (8) ◽  
pp. L797-L806 ◽  
Author(s):  
Kara N. Goss ◽  
Anthony R. Cucci ◽  
Amanda J. Fisher ◽  
Marjorie Albrecht ◽  
Andrea Frump ◽  
...  
Keyword(s):  
Lung Injury ◽  
Right Ventricular ◽  
Ventricular Remodeling ◽  
Systolic Pressure ◽  
Sprague Dawley ◽  
Hypoxia Exposure ◽  
Hyperoxia Exposure ◽  
Hyperoxic Lung Injury ◽  
Negative Impacts

The development of pulmonary hypertension (PH) requires multiple pulmonary vascular insults, yet the role of early oxygen therapy as an initial pulmonary vascular insult remains poorly defined. Here, we employ a two-hit model of PH, utilizing postnatal hyperoxia followed by adult hypoxia exposure, to evaluate the role of early hyperoxic lung injury in the development of later PH. Sprague-Dawley pups were exposed to 90% oxygen during postnatal days 0–4 or 0–10 or to room air. All pups were then allowed to mature in room air. At 10 wk of age, a subset of rats from each group was exposed to 2 wk of hypoxia (Patm = 362 mmHg). Physiological, structural, and biochemical endpoints were assessed at 12 wk. Prolonged (10 days) postnatal hyperoxia was independently associated with elevated right ventricular (RV) systolic pressure, which worsened after hypoxia exposure later in life. These findings were only partially explained by decreases in lung microvascular density. Surprisingly, postnatal hyperoxia resulted in robust RV hypertrophy and more preserved RV function and exercise capacity following adult hypoxia compared with nonhyperoxic rats. Biochemically, RVs from animals exposed to postnatal hyperoxia and adult hypoxia demonstrated increased capillarization and a switch to a fetal gene pattern, suggesting an RV more adept to handle adult hypoxia following postnatal hyperoxia exposure. We concluded that, despite negative impacts on pulmonary artery pressures, postnatal hyperoxia exposure may render a more adaptive RV phenotype to tolerate late pulmonary vascular insults.

Carbon monoxide provides protection against hyperoxic lung injury

1999 ◽  
Vol 276 (4) ◽  
pp. L688-L694 ◽  
Author(s):  
Leo E. Otterbein ◽  
Lin L. Mantell ◽  
Augustine M. K. Choi
Keyword(s):  
Oxidative Stress ◽  
Carbon Monoxide ◽  
Lung Injury ◽  
Neutrophil Infiltration ◽  
Protein Accumulation ◽  
Protective Effects ◽  
Low Concentration ◽  
Hyperoxic Lung Injury ◽  
Significant Attenuation

Findings in recent years strongly suggest that the stress-inducible gene heme oxygenase (HO)-1 plays an important role in protection against oxidative stress. Although the mechanism(s) by which this protection occurs is poorly understood, we hypothesized that the gaseous molecule carbon monoxide (CO), a major by-product of heme catalysis by HO-1, may provide protection against oxidative stress. We demonstrate here that animals exposed to a low concentration of CO exhibit a marked tolerance to lethal concentrations of hyperoxia in vivo. This increased survival was associated with highly significant attenuation of hyperoxia-induced lung injury as assessed by the volume of pleural effusion, protein accumulation in the airways, and histological analysis. The lungs were completely devoid of lung airway and parenchymal inflammation, fibrin deposition, and pulmonary edema in rats exposed to hyperoxia in the presence of a low concentration of CO. Furthermore, exogenous CO completely protected against hyperoxia-induced lung injury in rats in which endogenous HO enzyme activity was inhibited with tin protoporphyrin, a selective inhibitor of HO. Rats exposed to CO also exhibited a marked attenuation of hyperoxia-induced neutrophil infiltration into the airways and total lung apoptotic index. Taken together, our data demonstrate, for the first time, that CO can be therapeutic against oxidative stress such as hyperoxia and highlight possible mechanism(s) by which CO may mediate these protective effects.

scholarly journals Hepatic Estrogen Sulfotransferase Distantly Sensitizes Mice to Hemorrhagic Shock-Induced Acute Lung Injury

Endocrinology ◽  
2019 ◽  
Vol 161 (1) ◽  
Author(s):  
Yang Xie ◽  
Anne Caroline S Barbosa ◽  
Meishu Xu ◽  
Patrick J Oberly ◽  
Songrong Ren ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Hemorrhagic Shock ◽  
Pulmonary Inflammation ◽  
Neutrophil Infiltration ◽  
Estrogen Sulfotransferase ◽  
Tissue Specific ◽  
Genetic Ablation ◽  
Female Mice ◽  
Pharmacological Inhibition

Abstract Hemorrhagic shock (HS) is a potential life-threatening condition that may lead to injury to multiple organs, including the lung. The estrogen sulfotransferase (EST, or SULT1E1) is a conjugating enzyme that sulfonates and deactivates estrogens. In this report, we showed that the expression of Est was markedly induced in the liver but not in the lung of female mice subject to HS and resuscitation. Genetic ablation or pharmacological inhibition of Est effectively protected female mice from HS-induced acute lung injury (ALI), including interstitial edema, neutrophil mobilization and infiltration, and inflammation. The pulmonoprotective effect of Est ablation or inhibition was sex-specific, because the HS-induced ALI was not affected in male Est-/- mice. Mechanistically, the pulmonoprotective phenotype in female Est-/- mice was accompanied by increased lung and circulating levels of estrogens, attenuated pulmonary inflammation, and inhibition of neutrophil mobilization from the bone marrow and neutrophil infiltration to the lung, whereas the pulmonoprotective effect was abolished upon ovariectomy, suggesting that the protection was estrogen dependent. The pulmonoprotective effect of Est ablation was also tissue specific, as loss of Est had little effect on HS-induced liver injury. Moreover, transgenic reconstitution of human EST in the liver of global Est-/- mice abolished the pulmonoprotective effect, suggesting that it is the EST in the liver that sensitizes mice to HS-induced ALI. Taken together, our results revealed a sex- and tissue-specific role of EST in HS-induced ALI. Pharmacological inhibition of EST may represent an effective approach to manage HS-induced ALI.

Therapeutic effects of fibroblast grow factor 10 (FGF 10) after hyperoxic lung injury in mice

Pneumologie ◽  
2014 ◽  
Vol 68 (06) ◽  
Author(s):  
CM Chao ◽  
D Al Alam ◽  
R Schermuly ◽  
H Ehrhardt ◽  
KP Zimmer ◽  
...  
Keyword(s):  
Lung Injury ◽  
Therapeutic Effects ◽  
Hyperoxic Lung Injury
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