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This Article Full Text Full Text (PDF) All Versions of this Article: 296/5/L738    most recent 90603.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Nicola, T. Articles by Ambalavanan, N. Search for Related Content PubMed PubMed Citation Articles by Nicola, T. Articles by Ambalavanan, N.

Loss of Thy-1 inhibits alveolar development in the newborn mouse lung

Departments of ¹Pediatrics, ²Cell Biology, ³Pathology, ⁴Physiology and Biophysics, and ⁵Medicine, University of Alabama at Birmingham, Birmingham, Alabama

Submitted 5 December 2008 ; accepted in final form 3 March 2009

Transforming growth factor (TGF)-β mediates hypoxia-induced inhibition of alveolar development in the newborn lung. TGF-β is regulated primarily at the level of activation of latent TGF-β. Fibroblasts expressing Thy-1 (CD90) inhibit TGF-β activation. We hypothesized that loss of Thy-1 due to hypoxia may be a mechanism by which hypoxia increases TGF-β activation and that animals deficient in Thy-1 will simulate the effects of hypoxia on lung development. To determine if loss of Thy-1 occurred during hypoxia, non-transgenic (C57BL/6) wild-type (WT) mice exposed to hypoxia were evaluated for Thy-1 mRNA and protein. To determine if Thy-1 deficiency simulated hypoxia, WT and Thy-1 null (Thy-1^–/–) mice were exposed to air or hypoxia from birth to 2 wk, the critical period of lung development, and lung histology, function, parameters related to TGF-β signaling, and extracellular matrix protein content were measured. To test if the phenotype in Thy-1^–/– mice was due to excessive TGF-β signaling, measurements were also performed in Thy-1^–/– mice administered TGF-β neutralizing antibody (1D11). We observed that hypoxia reduced Thy-1 mRNA and Thy-1 staining in WT mice. Thy-1^–/– mice had impaired alveolarization, increased TGF-β signaling, reduced lung epithelial and endothelial cell proliferation but increased fibroblast proliferation, and increased collagen and elastin. Lung compliance was lower, and tissue but not airway resistance was higher in Thy-1^–/– mice at 2 wk. Thy-1^–/– mice given 1D11 had improved alveolar development and lung function. These data support the hypothesis that hypoxia, by reducing Thy-1, increases TGF-β activation, and thereby inhibits normal alveolar development.

transforming growth factor-β; infant; CD90