title: Hypoxia-induced inhibition of lung development is attenuated by the peroxisome proliferator-activated receptor-γ agonist rosiglitazone.
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.
authors.affiliation: Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.
authors.forename: Teodora
authors.initials: T
authors.lastname: Nicola
authors.forename: Namasivayam
authors.initials: N
authors.lastname: Ambalavanan
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Masheika L
authors.initials: ML
authors.lastname: James
authors.forename: Virender
authors.initials: V
authors.lastname: Rehan
authors.forename: Brian
authors.initials: B
authors.lastname: Halloran
authors.forename: Nelida
authors.initials: N
authors.lastname: Olave
authors.forename: Arlene
authors.initials: A
authors.lastname: Bulger
authors.forename: Suzanne
authors.initials: S
authors.lastname: Oparil
authors.forename: Yiu-Fai
authors.initials: YF
authors.lastname: Chen
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D017380:Hypertrophy, Right Ventricular / Q000150:complications / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D008168:Lung / Q000187:drug effects* / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D047495:PPAR gamma; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D000077154:Rosiglitazone; D003094:Collagen