Developmental regulation of p66Shc is altered by bronchopulmonary dysplasia in baboons and humans.
BACKGROUND
The p66(Shc) adapter protein antagonizes mitogen-activated protein, or MAP, kinase, mediates oxidative stress, and is developmentally regulated in fetal mouse lungs.


OBJECTIVE
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.


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
Matt K
MK
Center for Craniofacial Molecular Biology, School of Dentistry, University of Southren California, 2250 Alcazar Street, CSA-113, Los Angeles, CA 90033, USA. mattlee@usc.edu
Pryhuber
Gloria S
GS
Schwarz
Margaret A
MA
Smith
Susan M
SM
Pavlova
Zdena
Z
Sunday
Mary E
ME
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001997:Bronchopulmonary Dysplasia / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D005819:Genetic Markers / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D008168:Lung / Q000196:embryology*; D023421:Models, Animal; D010215:Papio; D011247:Pregnancy; D011270:Pregnancy, Animal; D012016:Reference Values; D055765:Shc Signaling Adaptor Proteins; D013045:Species Specificity; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D046509:Tissue Culture Techniques
D048868:Adaptor Proteins, Signal Transducing; D005819:Genetic Markers; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1