PMID- 14990357 OWN - NLM STAT- MEDLINE DCOM- 20041110 LR - 20220409 IS - 0891-5849 (Print) IS - 0891-5849 (Linking) VI - 36 IP - 6 DP - 2004 Mar 15 TI - Gene expression profile and histopathology of experimental bronchopulmonary dysplasia induced by prolonged oxidative stress. PG - 782-801 AB - 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. FAU - Wagenaar, Gerry T M AU - Wagenaar GT AD - Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, Netherlands. g.t.m.wagenaar@lumc.nl FAU - ter Horst, Simone A J AU - ter Horst SA FAU - van Gastelen, Margot A AU - van Gastelen MA FAU - Leijser, Lara M AU - Leijser LM FAU - Mauad, Thais AU - Mauad T FAU - van der Velden, Pieter A AU - van der Velden PA FAU - de Heer, Emile AU - de Heer E FAU - Hiemstra, Pieter S AU - Hiemstra PS FAU - Poorthuis, Ben J H M AU - Poorthuis BJ FAU - Walther, Frans J AU - Walther FJ LA - eng GR - R01 HL055534/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Free Radic Biol Med JT - Free radical biology & medicine JID - 8709159 RN - 0 (Blood Coagulation Factors) RN - 0 (RNA, Messenger) RN - 0 (Receptors, Fibroblast Growth Factor) RN - 9001-31-4 (Fibrin) RN - EC 2.7.10.1 (FGFR4 protein, human) RN - EC 2.7.10.1 (Fgfr4 protein, rat) RN - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 4) RN - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2) SB - IM MH - Animals MH - Animals, Newborn MH - Blood Coagulation Factors/genetics MH - Bronchopulmonary Dysplasia/chemically induced/genetics/*metabolism/*pathology MH - Extracellular Matrix/genetics/metabolism MH - Fibrin/metabolism MH - Fibrinolysis/genetics MH - Gene Expression Profiling MH - Humans MH - Infant, Newborn MH - Inflammation/genetics/metabolism MH - Lung/metabolism/*pathology MH - *Oxidative Stress MH - RNA, Messenger/*metabolism MH - Rats MH - Receptor, Fibroblast Growth Factor, Type 4 MH - Receptors, Fibroblast Growth Factor/genetics/metabolism MH - Signal Transduction/genetics MH - Vascular Endothelial Growth Factor Receptor-2/genetics/metabolism EDAT- 2004/03/03 05:00 MHDA- 2004/11/13 09:00 CRDT- 2004/03/03 05:00 PHST- 2003/07/01 00:00 [received] PHST- 2003/10/15 00:00 [revised] PHST- 2003/12/05 00:00 [accepted] PHST- 2004/03/03 05:00 [pubmed] PHST- 2004/11/13 09:00 [medline] PHST- 2004/03/03 05:00 [entrez] AID - S0891584903008554 [pii] AID - 10.1016/j.freeradbiomed.2003.12.007 [doi] PST - ppublish SO - Free Radic Biol Med. 2004 Mar 15;36(6):782-801. doi: 10.1016/j.freeradbiomed.2003.12.007.