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Hypoxia-induced inhibition of lung development is attenuated by the peroxisome proliferator-activated receptor-γ agonist rosiglitazone.
- Source :
-
American journal of physiology. Lung cellular and molecular physiology [Am J Physiol Lung Cell Mol Physiol] 2011 Jul; Vol. 301 (1), pp. L125-34. Date of Electronic Publication: 2011 Apr 29. - Publication Year :
- 2011
-
Abstract
- Hypoxia enhances transforming growth factor-β (TGF-β) signaling, inhibiting alveolar development and causing abnormal pulmonary arterial remodeling in the newborn lung. We hypothesized that, during chronic hypoxia, reduced peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling may contribute to, or be caused by, excessive TGF-β signaling. To determine whether PPAR-γ was reduced during hypoxia, C57BL/6 mice were exposed to hypoxia from birth to 2 wk and evaluated for PPAR-γ mRNA and protein. To determine whether rosiglitazone (RGZ, a PPAR-γ agonist) supplementation attenuated the effects of hypoxia, mice were exposed to air or hypoxia from birth to 2 wk in combination with either RGZ or vehicle, and measurements of lung histology, function, parameters related to TGF-β signaling, and collagen content were made. To determine whether excessive TGF-β signaling reduced PPAR-γ, mice were exposed to air or hypoxia from birth to 2 wk in combination with either TGF-β-neutralizing antibody or vehicle, and PPAR-γ signaling was evaluated. We observed that hypoxia reduced PPAR-γ mRNA and protein, in association with impaired alveolarization, increased TGF-β signaling, reduced lung compliance, and increased collagen. RGZ increased PPAR-γ signaling, with improved lung development and compliance in association with reduced collagen and TGF-β signaling. However, no reduction was noted in hypoxia-induced pulmonary vascular remodeling. Inhibition of hypoxia-enhanced TGF-β signaling increased PPAR-γ signaling. These results suggest that hypoxia-induced inhibition of lung development is associated with a mutually antagonistic relationship between reduced PPAR-γ and increased TGF-β signaling. PPAR-γ agonists may be of potential therapeutic significance in attenuating TGF-β signaling and improving alveolar development.
- Subjects :
- Airway Remodeling drug effects
Animals
Animals, Newborn
Antibodies, Neutralizing pharmacology
Chronic Disease
Collagen metabolism
Hypertrophy, Right Ventricular complications
Hypertrophy, Right Ventricular physiopathology
Hypoxia complications
Hypoxia physiopathology
Lung pathology
Lung physiopathology
Mice
Mice, Inbred C57BL
PPAR gamma metabolism
Pulmonary Alveoli drug effects
Pulmonary Alveoli metabolism
Pulmonary Alveoli pathology
Pulmonary Alveoli physiopathology
Rosiglitazone
Signal Transduction drug effects
Thiazolidinediones administration & dosage
Transforming Growth Factor beta metabolism
Hypoxia pathology
Lung drug effects
Lung growth & development
PPAR gamma agonists
Thiazolidinediones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1504
- Volume :
- 301
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Lung cellular and molecular physiology
- Publication Type :
- Academic Journal
- Accession number :
- 21531777
- Full Text :
- https://doi.org/10.1152/ajplung.00074.2011