Abstract |
We have previously shown that inhibition of transforming growth factor-β (TGF-β) signaling attenuates hypoxia-induced inhibition of alveolar development and abnormal pulmonary vascular remodeling in the newborn mice and that endothelin-A receptor (ETAR) antagonists prevent and reverse the vascular remodeling. The current study tested the hypothesis that inhibition of TGF-β signaling attenuates endothelin-1 (ET-1) expression and thereby reduces effects of hypoxia on the newborn lung. C57BL/6 mice were exposed from birth to 2 wk of age to either air or hypoxia (12% O(2)) while being given either BQ610 (ETAR antagonist), BQ788 (ETBR antagonist), 1D11 (TGF-β neutralizing antibody), or vehicle. Lung function and development and TGF-β and ET-1 synthesis were assessed. Hypoxia inhibited alveolar development, decreased lung compliance, and increased lung resistance. These effects were associated with increased TGF-β synthesis and signaling and increased ET-1 synthesis. BQ610 (but not BQ788) improved lung function, without altering alveolar development or increased TGF-β signaling in hypoxia-exposed animals. Inhibition of TGF-β signaling reduced ET-1 in vivo, which was confirmed in vitro in mouse pulmonary endothelial, fibroblast, and epithelial cells. ETAR blockade improves function but not development of the hypoxic newborn lung. Reduction of ET-1 via inhibition of TGF-β signaling indicates that TGF-β is upstream of ET-1 during hypoxia-induced signaling in the newborn lung.
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Authors | Nelida Olave, Teodora Nicola, Wei Zhang, Arlene Bulger, Masheika James, Suzanne Oparil, Yiu-Fai Chen, Namasivayam Ambalavanan |
Journal | American journal of physiology. Lung cellular and molecular physiology
(Am J Physiol Lung Cell Mol Physiol)
Vol. 302
Issue 9
Pg. L857-65
(May 01 2012)
ISSN: 1522-1504 [Electronic] United States |
PMID | 22287612
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Endothelin A Receptor Antagonists
- Endothelin B Receptor Antagonists
- Endothelin-1
- Oligopeptides
- Piperidines
- Receptor, Endothelin A
- Receptor, Endothelin B
- Transforming Growth Factor beta
- BQ 610
- BQ 788
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Topics |
- Animals
- Animals, Newborn
- Cells, Cultured
- Endothelial Cells
(metabolism)
- Endothelin A Receptor Antagonists
- Endothelin B Receptor Antagonists
- Endothelin-1
(genetics, metabolism, physiology)
- Endothelium, Vascular
(cytology)
- Gene Expression
- Hypoxia
(metabolism)
- Lung
(growth & development, metabolism, pathology, physiopathology)
- Mice
- Mice, Inbred C57BL
- Oligopeptides
(pharmacology)
- Piperidines
(pharmacology)
- Receptor, Endothelin A
(metabolism)
- Receptor, Endothelin B
(metabolism)
- Signal Transduction
- Transforming Growth Factor beta
(genetics, metabolism, physiology)
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