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Am J Physiol Lung Cell Mol Physiol (March 30, 2007). doi:10.1152/ajplung.00389.2006
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Submitted on October 3, 2006
Accepted on March 21, 2007

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

Hidehiko Nakanishi1, Takahiro Sugiura1, James B. Steisand2, Scott M. Lonning2, and Jesse David Roberts, Jr3*

1 Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts, United States; Cardiovascular Research Center, United States
2 Genzyme Corporation, Cambridge, Massachusetts, United States
3 Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts, United States; Pediatrics, Division of Newborn Medicine, United States; Cardiovascular Research Center, United States

* To whom correspondence should be addressed. E-mail: roberts{at}cvrc.mgh.harvard.edu.

Pulmonary injury is associated with the disruption of alveologenesis in the developing lung and causes bronchopulmonary dysplasia (BPD) in prematurely born infants. TGF-{beta} is an important regulator of cellular differentiation and early lung development and its levels are increased in newborn lung injury. Although over-expression 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 O2-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.




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