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Published on: December 11, 2020
Gene expression profile and histopathology of experimental bronchopulmonary dysplasia induced by prolonged oxidative
Gerry T M Wagenaar1, Simone A J ter Horst, Margôt A van Gastelen
1Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, Netherlands. g.t.m.wagenaar@lumc.nl
Insights
Oxidative stress in premature rat lungs causes significant gene expression changes, impacting inflammation and lung development, offering insights into bronchopulmonary dysplasia (BPD) pathogenesis.
Area of Science:
- Neonatal Physiology
- Pulmonary Medicine
- Molecular Biology
Background:
- Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants.
- Arrested alveolar and vascular development characterizes BPD.
- Oxidative stress is a key factor in BPD development.
Purpose of the Study:
- Investigate differential gene expression in premature rat lungs exposed to hyperoxia.
- Understand the role of oxidative stress in BPD pathogenesis.
- Identify key genes and pathways involved in BPD development.
Main Methods:
- DNA microarray analysis of premature rat lungs.
- Prolonged hyperoxia exposure during the saccular stage.
- Real-time RT-PCR, Western blotting, histopathology for confirmation.
Main Results:
- Hyperoxia induced complex gene expression changes related to inflammation, coagulation, and cell cycle.
- Significant fibrin deposition observed.
- Upregulation of genes like CINC-1, MCP-1, PAI-1, MMP12, and HO.
- Downregulation of FGFR4 and VEGF receptor-2 (Flk-1).
Conclusions:
- Oxidative stress significantly alters gene expression in developing lungs, contributing to BPD pathology.
- Findings provide fundamental insights into BPD pathophysiology.
- Identified genes and pathways are potential targets for novel therapeutic strategies.
Abstract:
Oxidative stress is an important factor in the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants characterized by arrested alveolar and vascular development of the immature lung. We investigated differential gene expression with DNA microarray analysis in premature rat lungs exposed to prolonged hyperoxia during the saccular stage of development, which closely resembles the development of the lungs of premature infants receiving neonatal intensive care. Expression profiles were largely confirmed by real-time RT-PCR (27 genes) and in line with histopathology and fibrin deposition studied by Western blotting. Oxidative stress affected a complex orchestra of genes involved in inflammation, coagulation, fibrinolysis, extracellular matrix turnover, cell cycle, signal transduction, and alveolar enlargement and explains, at least in part, the pathological alterations that occur in lungs developing BPD. Exciting findings were the magnitude of fibrin deposition; the upregulation of chemokine-induced neutrophilic chemoattractant-1 (CINC-1), monocyte chemoattractant protein-1 (MCP-1), amphiregulin, plasminogen activator inhibitor-1 (PAI-1), secretory leukocyte proteinase inhibitor (SLPI), matrix metalloproteinase-12 (MMP12), p21, metallothionein, and heme oxygenase (HO); and the downregulation of fibroblast growth factor receptor-4 (FGFR4) and vascular endothelial growth factor (VEGF) receptor-2 (Flk-1). These findings are not only of fundamental importance in the understanding of the pathophysiology of BPD, but also essential for the development of new therapeutic strategies.
