Changes in gene expression in hyperoxia-induced neonatal lung injury

Exposure to high concentrations of oxygen (hyperoxia) can result in lung injury. The biochemical basis of this injury is poorly understood, but it is likely to include alterations in gene expression. Hyperoxia-induced (H-I) cDNAs have been molecularly cloned (Horowitz et al. J. Biol. Chem. 264: 7092-7095, 1989) from the lungs of an adult rabbit exposed to toxic levels of oxygen. One of them (H-I 1) was identified as encoding the tissue inhibitor of metalloproteinases (TIMP), a key regulatory protein of extracellular matrix turnover. Here we identify another clone (H-I 3) as encoding pulmonary surfactant apoprotein A (SP-A). We also show that in neonatal rabbits exposed to 100% oxygen for 96 h, the mRNAs corresponding to TIMP, SP-A, and another H-I gene are increased. These studies have begun to explore specific changes in gene expression associated with neonatal hyperoxic lung injury.

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00230.2017 ◽

2017 ◽

Vol 313 (6) ◽

pp. L991-L1005 ◽

Cited By ~ 13

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.

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Analysis of the Transcriptome in Hyperoxic Lung Injury and Sex-Specific Alterations in Gene Expression

PLoS ONE ◽

10.1371/journal.pone.0101581 ◽

2014 ◽

Vol 9 (7) ◽

pp. e101581 ◽

Cited By ~ 16

Author(s):

Krithika Lingappan ◽

Chandra Srinivasan ◽

Weiwu Jiang ◽

Lihua Wang ◽

Xanthi I. Couroucli ◽

...

Keyword(s):

Gene Expression ◽

Lung Injury ◽

Hyperoxic Lung Injury

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Pathophysiology of Neonatal Lung Injury

International Journal of Technology Assessment in Health Care ◽

10.1017/s0266462300012514 ◽

1991 ◽

Vol 7 (S1) ◽

pp. 56-60

Author(s):

Richard D. Bland

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Ventilatory Support ◽

Fetal Lung ◽

Amniotic Cavity ◽

Pulmonary Endothelium ◽

Young Infants ◽

Neonatal Lung ◽

High Concentrations ◽

Protein Rich

Respiratory distress in newborn and young infants often develops as a result of acute lung injury, in which disruption of the normal barrier function of the pulmonary endothelium and epithelium causes protein-rich interstitial and alveolar edema. Several conditions may initiate acute lung injury, including aspiration of meconium or gastric contents, bacterial or viral infection, overzealous resuscitation, and birth associated with incomplete lung development that requires ventilatory support with positivepressure mechanical ventilation and high concentrations of inspired oxygen. The latter condition usually occurs after premature birth, but it also may occur as a consequence of impaired fetal lung growth secondary to diaphragmatic hernia or chest compression from lack of liquid in the amniotic cavity. Acute lung injury sometimes progresses to a chronic form of lung disease, which is characterized by edema, fibrosis, airway distortion, and nonuniform inflation of the lungs.

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

Pneumologie ◽

10.1055/s-0034-1376795 ◽

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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Faculty Opinions recommendation of A peroxynitrite decomposition catalyst prevents 60% O2-mediated rat chronic neonatal lung injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5045967.4981070 ◽

2010 ◽

Author(s):

Harry Ischiropoulos

Keyword(s):

Lung Injury ◽

Neonatal Lung ◽

Neonatal Lung Injury

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Faculty Opinions recommendation of Naturally occurring single amino acid replacements in a regulatory protein alter streptococcal gene expression and virulence in mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718116186.793484231 ◽

2014 ◽

Author(s):

Lars Malmstroem

Keyword(s):

Gene Expression ◽

Amino Acid ◽

Regulatory Protein ◽

Single Amino Acid ◽

Naturally Occurring

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Synergistic Effects of Aurothioglucose and Hyperoxia in Neonatal Hyperoxic Lung Injury

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2016.10.293 ◽

2016 ◽

Vol 100 ◽

pp. S113-S114

Author(s):

Stephanie Wall ◽

Rachael Tindell ◽

Katelyn Dunigan ◽

Rui Li ◽

Qian Li ◽

...

Keyword(s):

Lung Injury ◽

Synergistic Effects ◽

Hyperoxic Lung Injury

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Effects of rapamycin and OSI-027 on α-SMA in lung tissue of SD rat pups with hyperoxic lung injury

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2021.02.061 ◽

2021 ◽

Vol 556 ◽

pp. 39-44

Author(s):

Mulin Liang ◽

Hongxing Dang ◽

Qinghe Li ◽

Weiben Huang ◽

Chengjun Liu

Keyword(s):

Lung Injury ◽

Lung Tissue ◽

Rat Pups ◽

Sd Rat ◽

Hyperoxic Lung Injury

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DAX-1 Expression in Human Adrenocortical Neoplasms: Implications for Steroidogenesis

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.83.7.5095 ◽

1998 ◽

Vol 83 (7) ◽

pp. 2597-2600 ◽

Cited By ~ 17

Author(s):

M. Reincke ◽

F. Beuschlein ◽

E. Lalli ◽

W. Arlt ◽

S. Vay ◽

...

Keyword(s):

Gene Expression ◽

Mrna Expression ◽

Protein Gene ◽

Regulatory Protein ◽

Nuclear Hormone Receptor ◽

Adrenocortical Tumors ◽

Steroidogenic Acute Regulatory ◽

Adrenocortical Carcinomas ◽

Star Gene ◽

Functional Phenotype

The DAX-1 gene encodes an orphan nuclear hormone receptor essential for normal fetal development of the adrenal cortex. Recently, DAX-1 has been shown to act as a transcriptional repressor of steroidogenic acute regulatory protein gene expression (StAR), suppressing steroidogenesis. We, therefore, investigated the expression of DAX-1 in a variety of adrenocortical tumors and compared the results with StAR mRNA expression. We found low or absent DAX-1 expression in aldosterone-producing adenomas (n=11: 35±11%; normal adrenals: 100±17%) and in aldosterone-producing adrenocortical carcinomas (n=2: 24 and 36%). Cortisol-producing adenomas showed intermediate DAX-1 expression (n=8; 92±16), as did 3 non-aldosterone-producing carcinomas (72, 132 and 132%). High DAX-1 expression was present in nonfunctional adenomas (n=3; 160±17%). In contrast to DAX-1, StAR mRNA expression did not show significant variations between groups. We did not detect the expected negative correlation between DAX-1 and StAR mRNA in adrenocortical tumors. These data suggest that high DAX-1 expression in adrenocortical tumors is associated with a non-functional phenotype whereas low DAX-1 expression favors mineralo-corticoid secretion. These effects on steroidogenesis are mediated by mechanisms other than repression of StAR gene expression. Our results indicate that DAX-1 may be one of the factors influencing the steroid biosynthesis of adrenocortical neoplasms.

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