| Hyperoxia-induced neonatal rat lung injury involves activation of TGF-{beta} and Wnt signaling and is protected by rosiglitazone. | |
| | |
MedLine Citation:
|
PMID: 19304912 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Despite tremendous technological and therapeutic advances, bronchopulmonary dysplasia (BPD) remains a leading cause of respiratory morbidity in very low birth weight infants, and there are no effective preventive and/or therapeutic options. We have previously reported that hyperoxia-induced neonatal rat lung injury might be prevented by rosiglitazone (RGZ). Here, we characterize 1) perturbations in wingless/Int (Wnt) and transforming growth factor (TGF)-beta signaling, and 2) structural aberrations in lung morphology following 7-day continuous in vivo hyperoxia exposure to neonatal rats. We also tested whether treatment of neonatal pups with RGZ, concomitant to hyperoxia, could prevent such aberrations. Our study revealed that hyperoxia caused significant upregulation of Wnt signaling protein markers lymphoid enhancer factor 1 (Lef-1) and beta-catenin and TGF-beta pathway transducers phosphorylated Smad3 and Smad7 proteins in whole rat lung extracts. These changes were also accompanied by upregulation of myogenic marker proteins alpha-smooth muscle actin (alpha-SMA) and calponin but significant downregulation of the lipogenic marker peroxisome proliferator-activated receptor-gamma (PPARgamma) expression. These molecular perturbations were associated with reduction in alveolar septal thickness, radial alveolar count, and larger alveoli in the hyperoxia-exposed lung. These hyperoxia-induced molecular and morphological changes were prevented by systemic administration of RGZ, with lung sections appearing near normal. This is the first evidence that in vivo hyperoxia induces activation of both Wnt and TGF-beta signal transduction pathways in lung and of its near complete prevention by RGZ. Hyperoxia-induced arrest in alveolar development, a hallmark of BPD, along with these molecular changes strongly implicates these proteins in hyperoxia-induced lung injury. Administration of PPARgamma agonists may thus be a potential strategy to attenuate hyperoxia-induced lung injury and subsequent BPD. |
| | |
Authors:
|
Chiranjib Dasgupta; Reiko Sakurai; Ying Wang; Pinzheng Guo; Namasivayam Ambalavanan; John S Torday; Virender K Rehan |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-03-20 |
Journal Detail:
|
Title: American journal of physiology. Lung cellular and molecular physiology Volume: 296 ISSN: 1040-0605 ISO Abbreviation: Am. J. Physiol. Lung Cell Mol. Physiol. Publication Date: 2009 Jun |
Date Detail:
|
Created Date: 2009-05-29 Completed Date: 2009-07-16 Revised Date: 2012-09-18 |
Medline Journal Info:
|
Nlm Unique ID: 100901229 Medline TA: Am J Physiol Lung Cell Mol Physiol Country: United States |
Other Details:
|
Languages: eng Pagination: L1031-41 Citation Subset: IM |
Affiliation:
|
Departments of Pediatrics , Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA, David Geffen School of Medicine at UCLA, Torrance, California, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Actins
/
metabolism Acute Lung Injury / drug therapy, metabolism Age Factors Animals Animals, Newborn Calcium-Binding Proteins / metabolism Cells, Cultured Fibroblasts / cytology, drug effects, metabolism Hyperoxia / drug therapy*, metabolism* Hypoglycemic Agents / pharmacology Lac Operon Lymphoid Enhancer-Binding Factor 1 / metabolism Mice Mice, Transgenic Microfilament Proteins / metabolism PPAR gamma / metabolism Pulmonary Alveoli / cytology* Rats Rats, Sprague-Dawley Signal Transduction / drug effects, physiology Thiazolidinediones / pharmacology* Transforming Growth Factor beta / metabolism* Wnt Proteins / metabolism* beta Catenin / metabolism |
| Grant Support | |
ID/Acronym/Agency:
|
HD-051857/HD/NICHD NIH HHS; HL-075405/HL/NHLBI NIH HHS; HL-55268/HL/NHLBI NIH HHS; R01 HL092906-04/HL/NHLBI NIH HHS; R01 HL092906-05/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Actins; 0/Calcium-Binding Proteins; 0/Catnb protein, rat; 0/Hypoglycemic Agents; 0/Lef1 protein, rat; 0/Lymphoid Enhancer-Binding Factor 1; 0/Microfilament Proteins; 0/PPAR gamma; 0/Thiazolidinediones; 0/Transforming Growth Factor beta; 0/Wnt Proteins; 0/beta Catenin; 0/calponin; 122320-73-4/rosiglitazone |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Prolyl hydroxylase 2 deficiency limits proliferation of vascular smooth muscle cells by hypoxia-indu...
Next Document: PDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF-{beta}1-stimulated fibroblas...