Gene expression profile and histopathology of experimental bronchopulmonary dysplasia induced by prolonged oxidative stress.
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.
Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, Netherlands. g.t.m.wagenaar@lumc.nl
Gerry T M
GT
Wagenaar
Simone A J
SA
ter Horst
Margôt A
MA
van Gastelen
Lara M
LM
Leijser
Thais
T
Mauad
Pieter A
PA
van der Velden
Emile
E
de Heer
Pieter S
PS
Hiemstra
Ben J H M
BJ
Poorthuis
Frans J
FJ
Walther
D000818:Animals; D000831:Animals, Newborn; D001779:Blood Coagulation Factors / Q000235:genetics; D001997:Bronchopulmonary Dysplasia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D007231:Infant, Newborn; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D001779:Blood Coagulation Factors; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D005337:Fibrin; C496371:FGFR4 protein, human; C496373:Fgfr4 protein, rat; D051499:Receptor, Fibroblast Growth Factor, Type 4; D040301:Vascular Endothelial Growth Factor Receptor-2