Submitted on July 23, 2008
Revised on March 3, 2009
Accepted on March 5, 2009
Hyperoxia-Induced Neonatal Rat Lung Injury Involves Activation of TGF-
and Wnt Signaling, Protection by Rosiglitazone
Chiranjib Dasgupta1, Reiko Sakurai2, Ying Wang3, Pinzheng Guo3, Namasivayam Ambalavanan4, John S. Torday5, and Virender K Rehan6*
1 Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA
2 Los Angeles Biomedical Research Institute at Harbor UCLA Medical Center
3 Los Angeles Biomedical Research Institute
4 University of Alabama at Birmingham
5 Harbor-UCLA Medical Center
6 Harbor UCLA Medical Center
* To whom correspondence should be addressed. E-mail: vrehan{at}labiomed.org.
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 (a) perturbations in Wnt and TGF-
signaling, and (b) structural aberrations in lung morphology following 7-day continuous in vivo hyperoxia exposure to neonatal rats. We also tested if treatment of neonatal pups with RGZ, concomitant to hyperoxia, could prevent such aberrations. Our study revealed that hyperoxia caused significant up-regulation of Wnt signaling protein markers Lef-1 and -catenin, and TGF- pathway transducers pSMAD3 and SMAD7 proteins in whole rat lung extracts. These changes were also accompanied by up-regulation of myogenic marker proteins 
SMA and calponin, but significant down-regulation of the lipogenic marker PPAR
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 morphologic 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- signal transduction pathways in lung, and 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 PPAR agonists may thus be a potential strategy to attenuate hyperoxia-induced lung injury and subsequent BPD.
