title: TGF-beta-neutralizing antibodies improve pulmonary alveologenesis and vasculogenesis in the injured newborn lung.
abstract: 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.
authors.affiliation: Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, and Harvard Medical School, Cambridge, Massachusetts, USA.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Nakanishi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sugiura
authors.forename: James B
authors.initials: JB
authors.lastname: Streisand
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lonning
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Roberts
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D005260:Female; D018496:Hyperoxia / Q000473:pathology; D008171:Lung Diseases / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009500:Neutralization Tests; D010750:Phosphoproteins / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000254:growth & development* / Q000473:pathology*; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology*
chemical_list: D000906:Antibodies; D010750:Phosphoproteins; D020033:Protein Isoforms; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta; D004549:Elastin