HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Am J Physiol Lung Cell Mol Physiol 292: L537-L549, 2007. First published October 27, 2006; doi:10.1152/ajplung.00050.2006
1040-0605/07 $8.00

This Article Free upon publication Full Text Full Text (PDF) All Versions of this Article: 292/2/L537    most recent 00050.2006v1 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 ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (14) Citing Articles via Google Scholar Google Scholar Articles by Alejandre-Alcázar, M. A. Articles by Morty, R. E. Search for Related Content PubMed PubMed Citation Articles by Alejandre-Alcázar, M. A. Articles by Morty, R. E.

Hyperoxia modulates TGF-/BMP signaling in a mouse model of bronchopulmonary dysplasia

Departments of ¹Internal Medicine, ²Pathology, ³Paediatrics, and ⁴Biochemistry, University of Giessen Lung Center, Justus Liebig University, Giessen, Germany

Submitted 10 February 2006 ; accepted in final form 20 October 2006

Prematurely born infants who require oxygen therapy often develop bronchopulmonary dysplasia (BPD), a debilitating disorder characterized by pronounced alveolar hypoplasia. Hyperoxic injury is believed to disrupt critical signaling pathways that direct lung development, causing BPD. We investigated the effects of normobaric hyperoxia on transforming growth factor (TGF)- and bone morphogenetic protein (BMP) signaling in neonatal C57BL/6J mice exposed to 21% or 85% O₂ between postnatal days P1 and P28. Growth and respiratory compliance were significantly impaired in pups exposed to 85% O₂, and these pups also exhibited a pronounced arrest of alveolarization, accompanied by dysregulated expression and localization of both receptor (ALK-1, ALK-3, ALK-6, and the TGF- type II receptor) and Smad (Smads 1, 3, and 4) proteins. TGF- signaling was potentiated, whereas BMP signaling was impaired both in the lungs of pups exposed to 85% O₂ as well as in MLE-12 mouse lung epithelial cells and NIH/3T3 and primary lung fibroblasts cultured in 85% O₂. After exposure to 85% O₂, primary alveolar type II cells were more susceptible to TGF--induced apoptosis, whereas primary pulmonary artery smooth muscle cells were unaffected. Exposure of primary lung fibroblasts to 85% O₂ significantly enhanced the TGF--stimulated production of the ₁ subunit of type I collagen (I₁), tissue inhibitor of metalloproteinase-1, tropoelastin, and tenascin-C. These data demonstrated that hyperoxia significantly affects TGF-/BMP signaling in the lung, including processes central to septation and, hence, alveolarization. The amenability of these pathways to genetic and pharmacological manipulation may provide alternative avenues for the management of BPD.

lung development; transforming growth factor-; bone morphogenetic protein; neonatal chronic lung disease; alveolarization

This article has been cited by other articles:

				N. Ambalavanan, T. Nicola, J. Hagood, A. Bulger, R. Serra, J. Murphy-Ullrich, S. Oparil, and Y.-F. Chen Transforming growth factor-{beta} signaling mediates hypoxia-induced pulmonary arterial remodeling and inhibition of alveolar development in newborn mouse lung Am J Physiol Lung Cell Mol Physiol, July 1, 2008; 295(1): L86 - L95. [Abstract] [Full Text] [PDF]

				M. Myllarniemi, P. Lindholm, M. J. Ryynanen, C. R. Kliment, K. Salmenkivi, J. Keski-Oja, V. L. Kinnula, T. D. Oury, and K. Koli Gremlin-mediated Decrease in Bone Morphogenetic Protein Signaling Promotes Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., February 1, 2008; 177(3): 321 - 329. [Abstract] [Full Text] [PDF]

				R. D. Bland, R. Ertsey, L. M. Mokres, L. Xu, B. E. Jacobson, S. Jiang, C. M. Alvira, M. Rabinovitch, E. S. Shinwell, and A. Dixit Mechanical ventilation uncouples synthesis and assembly of elastin and increases apoptosis in lungs of newborn mice.: Prelude to defective alveolar septation during lung development? Am J Physiol Lung Cell Mol Physiol, January 1, 2008; 294(1): L3 - L14. [Abstract] [Full Text] [PDF]

				H. Hirakawa, R. A. Pierce, G. Bingol-Karakoc, C. Karaaslan, M. Weng, G.-P. Shi, A. Saad, E. Weber, T. J. Mariani, B. Starcher, et al. Cathepsin S Deficiency Confers Protection from Neonatal Hyperoxia-induced Lung Injury Am. J. Respir. Crit. Care Med., October 15, 2007; 176(8): 778 - 785. [Abstract] [Full Text] [PDF]

				H. Nakanishi, T. Sugiura, J. B. Streisand, S. M. Lonning, and J. D. Roberts Jr TGF-beta-neutralizing antibodies improve pulmonary alveologenesis and vasculogenesis in the injured newborn lung Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L151 - L161. [Abstract] [Full Text] [PDF]

				A. Zakrzewicz, M. Hecker, L. M. Marsh, G. Kwapiszewska, B. Nejman, L. Long, W. Seeger, R. T. Schermuly, N. W. Morrell, R. E. Morty, et al. Receptor for Activated C-Kinase 1, a Novel Interaction Partner of Type II Bone Morphogenetic Protein Receptor, Regulates Smooth Muscle Cell Proliferation in Pulmonary Arterial Hypertension Circulation, June 12, 2007; 115(23): 2957 - 2968. [Abstract] [Full Text] [PDF]

				A. Zakrzewicz, F. M. Kouri, B. Nejman, G. Kwapiszewska, M. Hecker, R. Sandu, E. Dony, W. Seeger, R. T. Schermuly, O. Eickelberg, et al. The transforming growth factor-{beta}/Smad2,3 signalling axis is impaired in experimental pulmonary hypertension Eur. Respir. J., June 1, 2007; 29(6): 1094 - 1104. [Abstract] [Full Text] [PDF]