Published ahead of print on March 18, 2005, doi:10.1164/rccm.200406-776OC Am. J. Respir. Crit. Care Med., Volume 171, Number 12, June 2005, 1384-1394 A more recent version of this article appeared on June 15, 2005
Submitted on June 18, 2004 Developmental Regulation of p66Shc is Altered by Bronchopulmonary Dysplasia in Baboons and HumansMatt K Lee1*,1 Center for Craniofacial Molecular Biology, University of Southern California, School of Dentistry, Los Angeles, CA, USA; Neonatology Division, Department of Pediatrics, University of Southern California/Los Angeles County Medical Center, Los Angeles, CA, USA, 2 Department of Pediatrics, Golisano Children's Hospital at Strong, University of Rochester Medical Center, Rochester, NY, USA, 3 Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ, USA, 4 Center for Craniofacial Molecular Biology, University of Southern California, School of Dentistry, Los Angeles, CA, USA, 5 Departments of Pathology and Pediatrics, University of Southern California/Los Angeles County Medical Center, Los Angeles, CA, USA, 6 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA * To whom correspondence should be addressed. E-mail: mattlee{at}usc.,edu.
Rationale: The p66Shc adapter protein antagonizes MAP kinase, mediates oxidative stress, and is developmentally regulated in fetal mouse lungs. Objectives: Determine if p66Shc is similarly regulated in primates and in bronchopulmonary dysplasia, 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 bronchopulmonary dysplasia 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 anti-bombesin antibody 2A11 attenuated bronchopulmonary dysplasia, 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 bronchopulmonary dysplasia, 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 bronchopulmonary dysplasia. Key words: lung, fetal development, ShcA protein, MAP kinases
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