Published ahead of print on March 18, 2005, doi:10.1164/rccm.200406-776OC
© 2005 American Thoracic Society doi: 10.1164/rccm.200406-776OC
Developmental Regulation of p66Shc Is Altered by Bronchopulmonary Dysplasia in Baboons and HumansCenter for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, and the Neonatology Division, Departments of Pediatrics and Pathology, University of Southern California/Los Angeles County Medical Center, Los Angeles, California; Department of Pediatrics, Golisano Children's Hospital at Strong, University of Rochester Medical Center, Rochester, New York; Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey; and Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts Correspondence and requests for reprints should be addressed to Matt Lee, M.D., USC CCMB, 2250 Alcazar Street, CSA-113, Los Angeles, CA 90033. E-mail: mattlee{at}usc.edu Rationale: The p66Shc adapter protein antagonizes mitogen-activated protein, or MAP, kinase, mediates oxidative stress, and is developmentally regulated in fetal mouse lungs. Objectives: To determine if p66Shc is similarly regulated in primates and in bronchopulmonary dysplasia (BPD), which results from oxidative injury to immature lungs. Methods: Normal and injured lungs from humans and baboons were evaluated by Western analysis and immunohistochemistry. Measurements and Main Results: In baboons, p66Shc decreased 80% between 125 and 175 days' gestation (p = 0.025), then doubled after term delivery at 185 days (p = 0.0013). In the hyperoxic 140-day fetal baboon BPD model, p66Shc expression persisted, and its localization shifted from the epithelium of gestational controls to the mesenchyme of diseased lungs, coincident with expression of proliferating cell nuclear antigen and cleaved poly(adenyl ribose) polymerase, a marker of apoptosis. Treatment with the antibombesin antibody 2A11 attenuated BPD, reduced cell proliferation, increased p66Shc expression 10.5-fold, and preserved epithelial p66Shc localization. p66Shc also decreased during normal human lung development, falling 87% between 18 and 24 weeks' gestation (p = 0.02). p66Shc was expressed throughout 18-week human lungs, became restricted to scattered epithelial cells by 24 weeks, and localized to isolated mesenchymal cells after term delivery. In contrast, p66Shc remained prominent in the epithelium of lungs with acute injury or mild BPD, and in the mesenchyme of lungs with severe disease. p66Shc localized to tissues expressing proliferating cell nuclear antigen and cleaved poly(adenyl ribose) polymerase. Conclusions: p66Shc expression, cell proliferation, and apoptosis are concomitantly altered during lung development and in BPD.
Key Words: fetal development • lung • MAP kinases • ShcA protein This article has been cited by other articles:
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