Dataset Information

Sphingosine kinase 1 regulates lysyl oxidase through STAT3 in hyperoxia-mediated neonatal lung injury.

ABSTRACT:

Introduction

Neonatal lung injury as a consequence of hyperoxia (HO) therapy and ventilator care contribute to the development of bronchopulmonary dysplasia (BPD). Increased expression and activity of lysyl oxidase (LOX), a key enzyme that cross-links collagen, was associated with increased sphingosine kinase 1 (SPHK1) in human BPD. We, therefore, examined closely the link between LOX and SPHK1 in BPD.

Method

The enzyme expression of SPHK1 and LOX were assessed in lung tissues of human BPD using immunohistochemistry and quantified (Halo). In vivo studies were based on Sphk1^-/- and matched wild type (WT) neonatal mice exposed to HO while treated with PF543, an inhibitor of SPHK1. In vitro mechanistic studies used human lung microvascular endothelial cells (HLMVECs).

Results

Both SPHK1 and LOX expressions were increased in lungs of patients with BPD. Tracheal aspirates from patients with BPD had increased LOX, correlating with sphingosine-1-phosphate (S1P) levels. HO-induced increase of LOX in lungs were attenuated in both Sphk1^-/- and PF543-treated WT mice, accompanied by reduced collagen staining (sirius red). PF543 reduced LOX activity in both bronchoalveolar lavage fluid and supernatant of HLMVECs following HO. In silico analysis revealed STAT3 as a potential transcriptional regulator of LOX. In HLMVECs, following HO, ChIP assay confirmed increased STAT3 binding to LOX promoter. SPHK1 inhibition reduced phosphorylation of STAT3. Antibody to S1P and siRNA against SPNS2, S1P receptor 1 (S1P₁) and STAT3 reduced LOX expression.

Conclusion

HO-induced SPHK1/S1P signalling axis plays a critical role in transcriptional regulation of LOX expression via SPNS2, S1P₁ and STAT3 in lung endothelium.

SUBMITTER: Ha AW

PROVIDER: S-EPMC9115769 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Publications

Sphingosine kinase 1 regulates lysyl oxidase through STAT3 in hyperoxia-mediated neonatal lung injury.

Ha Alison W AW Bai Tao T Ebenezer David L DL Sethi Tanvi T Sudhadevi Tara T Mangio Lizar Ace LA Garzon Steven S Pryhuber Gloria S GS Natarajan Viswanathan V Harijith Anantha A

Thorax 20210421 1

<h4>Introduction</h4>Neonatal lung injury as a consequence of hyperoxia (HO) therapy and ventilator care contribute to the development of bronchopulmonary dysplasia (BPD). Increased expression and activity of lysyl oxidase (LOX), a key enzyme that cross-links collagen, was associated with increased sphingosine kinase 1 (SPHK1) in human BPD. We, therefore, examined closely the link between LOX and SPHK1 in BPD.<h4>Method</h4>The enzyme expression of SPHK1 and LOX were assessed in lung tissues of ...[more]

PMID: 33883249

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Project description:Preterm infants and patients with lung disease often have excess fluid in the lungs and are frequently treated with oxygen, however long-term exposure to hyperoxia results in irreversible lung injury. Although the adverse effects of hyperoxia are mediated by reactive oxygen species, the full extent of the impact of hyperoxia on redox-dependent regulation in the lung is unclear. In this study, neonatal mice overexpressing the beta-subunit of the epithelial sodium channel (β-ENaC) encoded by Scnn1b and their wild type (WT; C57Bl6) littermates were utilized to study the pathogenesis of high fraction inspired oxygen (FiO2)-induced lung injury. Results showed that O2-induced lung injury in transgenic Scnn1b mice is attenuated following chronic O2 exposure. To test the hypothesis that reversible cysteine-redox-modifications of proteins play an important role in O2-induced lung injury, we performed proteome-wide profiling of protein S-glutathionylation (SSG) in both WT and Scnn1b overexpressing mice maintained at 21% O2 (normoxia) or FiO2 85% (hyperoxia) from birth to 11-15 days postnatal. Over 7700 unique Cys sites with SSG modifications were identified and quantified, covering more than 3000 proteins in the lung. In both mouse models, hyperoxia resulted in a significant alteration of the SSG levels of Cys sites belonging to a diverse range of proteins. In addition, substantial SSG changes were observed in the Scnn1b overexpressing mice exposed to hyperoxia, suggesting that ENaC plays a critically important role in cellular regulation. Hyperoxia-induced SSG changes were further supported by the results observed for thiol total oxidation, the overall level of reversible oxidation on protein cysteine residues. Differential analyses reveal that Scnn1b overexpression may protect against hyperoxia-induced lung injury via modulation of specific processes such as cell adhesion, blood coagulation, and proteolysis. This study provides a landscape view of protein oxidation in the lung and highlights the importance of redox regulation in O2-induced lung injury.

Project description:BackgroundPremature born infants are at high risk to develop white matter injury (WMI). Hyperoxia and perinatal inflammation are main risk factors for preterm birth and associated brain injury. To date the majority of experimental studies have focused on isolated insults. However, clinically, WMI injury is a multifactorial disorder caused by a variety of triggers. To establish a clinically relevant rodent model of WMI, we combined prenatal inflammation with postnatal hyperoxia to investigate individual, and additive or synergistic effects on inflammatory processes, myelination and grey matter development.MethodsAt embryonic day 20, pregnant Wistar rat dams received either a single intraperitoneal injection of 100 µg/ kg lipopolysaccharide (LPS) or sodium chloride. Offspring were either exposed to hyperoxia (80% O2) or normoxia (21% O2) from postnatal day 3 to 5. Animals were sacrificed immediately after hyperoxia or 6 days later, corresponding to term-equivalent age. White and grey matter development and neuroinflammatory responses were investigated at cellular and molecular levels applying immunohistochemistry, western blotting, real time PCR in brain tissues and multiplex protein expression analysis on serum samples.ResultsPrenatal inflammation combined with postnatal hyperoxia resulted in reduced body weight and length in the offspring, accompanied by increased serum leptin levels at term equivalent age. The altered body parameters, like body weight, were associated with decreased brain volume, thinning of deep cortical layers and hypomyelination. As potential underlying mechanisms, we identified severe myelination deficits and an increased microglia activation associated with elevated inflammatory cytokine expression in brain tissues, while peripheral cytokine levels were reduced. Interestingly, effects on body size were mainly mediated by prenatal LPS, independent of hyperoxia, while oligodendrocyte degeneration was mainly induced by postnatal hyperoxia, independent of prenatal inflammation. However, for the majority of pathological changes, including brain size, myelination deficits, microglia activation and inflammatory cytokine expression, additive or synergistic effects were detected.ConclusionPrenatal inflammation combined with postnatal hyperoxia results in aggravated myelination deficits and inflammatory responses compared to single insults, making it an ideal model to improve our understanding of the complex pathophysiology underlying WMI and to evaluate urgently needed therapies.

Dataset Information

Sphingosine kinase 1 regulates lysyl oxidase through STAT3 in hyperoxia-mediated neonatal lung injury.

Introduction

Method

Results

Conclusion

Publications

Sphingosine kinase 1 regulates lysyl oxidase through STAT3 in hyperoxia-mediated neonatal lung injury.

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