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Articles in PresS, published online ahead of print May 3, 2002
J Appl Physiol, 10.1152/jap.00031.2002
Submitted on January 15, 2002
Accepted on April 30, 2002
1 Departments of Pediatrics (Section of Respiratory Medicine), Yale University School of Medicine, New Haven, CT, USA
2 Departments of Pathology, Yale University School of Medicine, New Haven, CT, USA
* To whom correspondence should be addressed. E-mail: gabriel.haddad{at}yale.edu.
Hypoxia regulates normal organogenesis and vasculogenesis, but also contributes to the pathophysiology of multiple diseases. Long-term effects of hypoxia are largely due to its modulatory effects on proliferation and differentiation of epithelial and endothelial cells, processes also regulated by the transforming growth factor (TGF)-ß system. In this study, we investigated the effects of chronic hypoxia on TGF-ß activity and TGF-ß receptor (TßR) isotype expression in rat lungs obtained at different developmental stages. Sprague-Dawley rats were exposed to hypoxia (9.5% oxygen) beginning at postnatal day (P) 3 and sacrificed at P14. Similarly, adult rats raised in room air were placed in hypoxia for two weeks. Histologic examination and quantitative analysis of septal number and thickness revealed an arrest of alveolar formation in P14 rats, but not adult animals exposed to hypoxia. At P14, bioactive TGF-ß levels in bronchoalveolar lavage fluid were increased in hypoxic animals compared with controls, whereas no changes were observed in adults. Western blot analysis of whole lung tissue revealed specific up-regulation of TßRI and TßRII in response to hypoxia at P14, but not in adults. In contrast, hypoxia led to decreased expression of TßRIII in both P14 and adult rats. Immunohistochemical analysis localized TßRI, TßRII and TßRIII expression predominately to bronchiolar and alveolar epithelium, although less intense staining was also seen in endothelium. The localization patterns of each receptor did not change with hypoxia, but the staining intensity of TßRI and TßRII increased, especially in airway and alveolar cells. In sum, we observed significant changes in both TGF-ß activity and TßR isotype expression in rat lung that parallel the arrest in alveolarization seen with exposure to chronic hypoxia early in development. Alteration of TGF-ß signaling may therefore explain some of the morphologic changes observed in hypoxia.
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