Developmental regulation of p66Shc is altered by bronchopulmonary dysplasia in baboons and humans.
RATIONALE: The p66(Shc) adapter protein antagonizes mitogen-activated protein, or MAP, kinase, mediates oxidative stress, and is developmentally regulated in fetal mouse lungs. OBJECTIVES: To determine if p66(Shc) 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, p66(Shc) 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, p66(Shc) 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 p66(Shc) expression 10.5-fold, and preserved epithelial p66(Shc) localization. p66(Shc) also decreased during normal human lung development, falling 87% between 18 and 24 weeks' gestation (p = 0.02). p66(Shc) 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, p66(Shc) remained prominent in the epithelium of lungs with acute injury or mild BPD, and in the mesenchyme of lungs with severe disease. p66(Shc) localized to tissues expressing proliferating cell nuclear antigen and cleaved poly(adenyl ribose) polymerase. CONCLUSIONS: p66(Shc) expression, cell proliferation, and apoptosis are concomitantly altered during lung development and in BPD.
Lee, MK; Pryhuber, GS; Schwarz, MA; Smith, SM; Pavlova, Z; Sunday, ME
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