title: Hyperoxia-induced neonatal rat lung injury involves activation of TGF-{beta} and Wnt signaling and is protected by rosiglitazone.
abstract: 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.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.
authors.forename: Chiranjib
authors.initials: C
authors.lastname: Dasgupta
authors.forename: Reiko
authors.initials: R
authors.lastname: Sakurai
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Pinzheng
authors.initials: P
authors.lastname: Guo
authors.forename: Namasivayam
authors.initials: N
authors.lastname: Ambalavanan
authors.forename: John S
authors.initials: JS
authors.lastname: Torday
authors.forename: Virender K
authors.initials: VK
authors.lastname: Rehan
mesh_terms: D000199:Actins / Q000378:metabolism; D055371:Acute Lung Injury / Q000188:drug therapy / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018496:Hyperoxia / Q000188:drug therapy* / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007763:Lac Operon; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D000096985:Calponins
chemical_list: D000199:Actins; D002135:Calcium-Binding Proteins; D007004:Hypoglycemic Agents; D051821:Lymphoid Enhancer-Binding Factor 1; D008840:Microfilament Proteins; D047495:PPAR gamma; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D051176:beta Catenin; D000096985:Calponins; C495268:Ctnnb1 protein, rat; C497575:Lef1 protein, rat