Document Detail


Antenatal imatinib treatment reduces pulmonary vascular remodeling in a rat model of congenital diaphragmatic hernia.
MedLine Citation:
PMID:  22447953     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The pathophysiology of congenital diaphragmatic hernia (CDH) is constituted by pulmonary hypoplasia and pulmonary hypertension (PH). We previously reported successful treatment with imatinib of a patient with CDH. This study examines the effect of antenatal imatinib administration on the pulmonary vasculature in a rat model of CDH. Pregnant rats were given nitrofen to induce CDH. Controls were given olive oil. Half of the CDH fetuses and half of the controls were treated with imatinib antenatally E17-E21, rendering four groups: Control, Control+Imatinib, CDH, and CDH+Imatinib. Lung sections were obtained for morphometry and immunohistochemistry, and protein was purified for Western blot. Effects of nitrofen and imatinib on Ki-67, caspase-3, PDGF-B, and PDGF receptors were analyzed. Imatinib significantly reduced medial wall thickness in pulmonary arteries of rats with CDH. It also normalized lumen area and reduced the proportion of fully muscularized arteries. Imatinib also caused medial thinning in the control group. Cell proliferation was increased in CDH, and this proliferation was significantly reduced by imatinib. PDGF-B and PDGFR-β were upregulated in CDH, and imatinib treatment resulted in a downregulation. PDGFR-α remained unchanged in CDH but was significantly downregulated by imatinib. Antenatal imatinib treatment reduces development of medial wall thickness and restores lumen area in pulmonary arteries in nitrofen-induced CDH. The mechanism is reduced cell proliferation. Imatinib is an interesting candidate for antenatal therapy for PH in CDH, but potential side effects need to be investigated and more specific targeting of PDGF signaling is needed.
Authors:
Ya-Ting Chang; Andreas Ringman Uggla; Cecilia Osterholm; Phan-Kiet Tran; Ann-Christine Eklöf; Mariette Lengquist; Ulf Hedin; Karin Tran-Lundmark; Björn Frenckner
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-03-23
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  302     ISSN:  1522-1504     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-06-04     Completed Date:  2012-08-07     Revised Date:  2012-08-30    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L1159-66     Citation Subset:  IM    
Affiliation:
Division of Pediatrics, Department of Women’s and Children’s Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
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MeSH Terms
Descriptor/Qualifier:
Airway Remodeling / drug effects
Animals
Apoptosis / drug effects
Caspase 3 / biosynthesis
Cell Proliferation / drug effects
Disease Models, Animal
Female
Hernia, Diaphragmatic / chemically induced,  congenital*,  drug therapy,  pathology,  physiopathology
Ki-67 Antigen / biosynthesis
Lung / blood supply*,  drug effects,  pathology*
Phenyl Ethers / pharmacology
Piperazines / pharmacology*
Platelet-Derived Growth Factor / biosynthesis
Pregnancy
Pulmonary Artery / drug effects,  pathology
Pyrimidines / pharmacology*
RNA, Messenger / genetics,  metabolism
Rats
Rats, Sprague-Dawley
Receptors, Platelet-Derived Growth Factor / biosynthesis
Chemical
Reg. No./Substance:
0/Ki-67 Antigen; 0/Phenyl Ethers; 0/Piperazines; 0/Platelet-Derived Growth Factor; 0/Pyrimidines; 0/RNA, Messenger; 152459-95-5/imatinib; 1836-75-5/nitrofen; EC 2.7.10.1/Receptors, Platelet-Derived Growth Factor; EC 3.4.22.-/Caspase 3

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