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

¹Department of Anesthesia and Critical Care and ²Division of Newborn Medicine in the Department of Pediatrics, and ³Cardiovascular Research Center, Massachusetts General Hospital, Boston, and Harvard Medical School, Cambridge; and ⁴Genzyme Corporation, Cambridge, Massachusetts

Submitted 3 October 2006 ; accepted in final form 21 March 2007

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)- is an important regulator of cellular differentiation and early lung development, and its levels are increased in newborn lung injury. Although overexpression of TGF- in the lungs of newborn animals causes pathological features that are consistent with BPD, the role of endogenous TGF- 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--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--neutralizing antibodies attenuates the increase in pulmonary cell phospho-Smad2 nuclear localization, which is indicative of augmented TGF- signaling, associated with pulmonary injury induced by chronic inhalation of 85% oxygen. Importantly, the neutralization of the abnormal TGF- activity improves quantitative morphometric indicators of alveologenesis, extracellular matrix assembly, and microvascular development in the injured developing lung. Furthermore, exposure to anti-TGF- 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- 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- antibodies may be an effective therapy for preventing some important developmental diseases of the newborn lung.

bronchopulmonary dysplasia; transforming growth factor-

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