TGF-beta-neutralizing antibodies improve pulmonary alveologenesis and vasculogenesis in the injured newborn lung

Am J Physiol Lung Cell Mol Physiol. 2007 Jul;293(1):L151-61. doi: 10.1152/ajplung.00389.2006. Epub 2007 Mar 30.


Pulmonary injury is associated with the disruption of alveologenesis in the developing lung and causes bronchopulmonary dysplasia (BPD) in prematurely born infants. Transforming growth factor (TGF)-beta is an important regulator of cellular differentiation and early lung development, and its levels are increased in newborn lung injury. Although overexpression of TGF-beta in the lungs of newborn animals causes pathological features that are consistent with BPD, the role of endogenous TGF-beta in the inhibition of the terminal stage of lung development is incompletely understood. In this investigation, the hypothesis that O(2)-induced injury of the maturing lung is associated with TGF-beta-mediated disruption of alveologenesis and microvascular development was tested using a murine model of BPD. Here we report that treatment of developing mouse lungs with TGF-beta-neutralizing antibodies attenuates the increase in pulmonary cell phospho-Smad2 nuclear localization, which is indicative of augmented TGF-beta signaling, associated with pulmonary injury induced by chronic inhalation of 85% oxygen. Importantly, the neutralization of the abnormal TGF-beta activity improves quantitative morphometric indicators of alveologenesis, extracellular matrix assembly, and microvascular development in the injured developing lung. Furthermore, exposure to anti-TGF-beta antibodies is associated with improved somatic growth in hyperoxic mouse pups and not with an increase in pulmonary inflammation. These studies indicate that excessive pulmonary TGF-beta signaling in the injured newborn lung has an important role in the disruption of the terminal stage of lung development. In addition, they suggest that anti-TGF-beta antibodies may be an effective therapy for preventing some important developmental diseases of the newborn lung.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Antibodies / pharmacology*
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Elastin / metabolism
  • Female
  • Hyperoxia / pathology
  • Lung Diseases / pathology
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic / drug effects*
  • Neutralization Tests
  • Phosphoproteins / metabolism
  • Protein Isoforms / metabolism
  • Protein Transport / drug effects
  • Pulmonary Alveoli / blood supply
  • Pulmonary Alveoli / growth & development*
  • Pulmonary Alveoli / pathology*
  • Smad2 Protein / metabolism
  • Transforming Growth Factor beta / immunology*


  • Antibodies
  • Phosphoproteins
  • Protein Isoforms
  • Smad2 Protein
  • Smad2 protein, mouse
  • Transforming Growth Factor beta
  • Elastin