Developmental regulation of p66Shc is altered by bronchopulmonary dysplasia in baboons and humans

Matt K. Lee, Gloria S. Pryhuber, Margaret Schwarz, Susan M. Smith, Zdena Pavlova, Mary E. Sunday

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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. 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.

Original languageEnglish (US)
Pages (from-to)1384-1394
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume171
Issue number12
DOIs
StatePublished - Jun 15 2005
Externally publishedYes

Fingerprint

Bronchopulmonary Dysplasia
Papio
Lung
Ribose
Proliferating Cell Nuclear Antigen
Mesoderm
Accidental Falls
Epithelium
Cell Proliferation
Apoptosis
Pregnancy
Acute Lung Injury
Human Development
Mitogens
Primates
Lung Diseases
Proteins
Oxidative Stress
Phosphotransferases
Epithelial Cells

Keywords

  • Fetal development
  • Lung
  • MAP kinases
  • ShcA protein

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Developmental regulation of p66Shc is altered by bronchopulmonary dysplasia in baboons and humans. / Lee, Matt K.; Pryhuber, Gloria S.; Schwarz, Margaret; Smith, Susan M.; Pavlova, Zdena; Sunday, Mary E.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 171, No. 12, 15.06.2005, p. 1384-1394.

Research output: Contribution to journalArticle

Lee, Matt K. ; Pryhuber, Gloria S. ; Schwarz, Margaret ; Smith, Susan M. ; Pavlova, Zdena ; Sunday, Mary E. / Developmental regulation of p66Shc is altered by bronchopulmonary dysplasia in baboons and humans. In: American Journal of Respiratory and Critical Care Medicine. 2005 ; Vol. 171, No. 12. pp. 1384-1394.
@article{073930bfafe4406399f9322afedada14,
title = "Developmental regulation of p66Shc is altered by bronchopulmonary dysplasia in baboons and humans",
abstract = "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. 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.",
keywords = "Fetal development, Lung, MAP kinases, ShcA protein",
author = "Lee, {Matt K.} and Pryhuber, {Gloria S.} and Margaret Schwarz and Smith, {Susan M.} and Zdena Pavlova and Sunday, {Mary E.}",
year = "2005",
month = "6",
day = "15",
doi = "10.1164/rccm.200406-776OC",
language = "English (US)",
volume = "171",
pages = "1384--1394",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "12",

}

TY - JOUR

T1 - Developmental regulation of p66Shc is altered by bronchopulmonary dysplasia in baboons and humans

AU - Lee, Matt K.

AU - Pryhuber, Gloria S.

AU - Schwarz, Margaret

AU - Smith, Susan M.

AU - Pavlova, Zdena

AU - Sunday, Mary E.

PY - 2005/6/15

Y1 - 2005/6/15

N2 - 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. 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.

AB - 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. 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.

KW - Fetal development

KW - Lung

KW - MAP kinases

KW - ShcA protein

UR - http://www.scopus.com/inward/record.url?scp=20444397740&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20444397740&partnerID=8YFLogxK

U2 - 10.1164/rccm.200406-776OC

DO - 10.1164/rccm.200406-776OC

M3 - Article

C2 - 15778491

AN - SCOPUS:20444397740

VL - 171

SP - 1384

EP - 1394

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 12

ER -