Uteroplacental insufficiency decreases p53 serine-15 phosphorylation in term IUGR rat lungs.
Intrauterine growth restriction (IUGR) increases the incidence of chronic lung disease (CLD). The molecular mechanisms responsible for IUGR-induced acute lung injury that predispose the IUGR infant to CLD are unknown. p53, a transcription factor, plays a pivotal role in determining cellular response to stress by affecting apoptosis, cell cycle regulation, and angiogenesis, processes required for thinning of lung mesenchyme. Because thickened lung mesenchyme is characteristic of CLD, we hypothesized that IUGR-induced changes in lung growth are associated with alterations in p53 expression and/or modification. We induced IUGR through bilateral uterine artery ligation of pregnant rats. Uteroplacental insufficiency significantly decreased serine-15-phosphorylated (serine-15P) p53, an active form of p53, in IUGR rat lung. Moreover, we found that decreased phosphorylation of lung p53 serine-15 localized to thickened distal air space mesenchyme. We also found that IUGR significantly decreased mRNA for targets downstream of p53, specifically, proapoptotic Bax and Apaf, as well as Gadd45, involved in growth arrest, and Tsp-1, involved in angiogenesis. Furthermore, we found that IUGR significantly increased mRNA for Bcl-2, an antiapoptotic gene downregulated by p53. We conclude that in IUGR rats, uteroplacental insufficiency induces decreased lung mesenchymal p53 serine-15P in association with distal lung mesenchymal thickening. We speculate that decreased p53 serine-15P in IUGR rat lungs alters lung phenotype, making the IUGR lung more susceptible to subsequent injury.
O'Brien
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EA
Division of Neonatology, University of Utah, Salt Lake City, UT 84158, USA. elizabeth.obrien@hsc.utah.edu
Barnes
V
V
Zhao
L
L
McKnight
R A
RA
Yu
X
X
Callaway
C W
CW
Wang
L
L
Sun
J C
JC
Dahl
M J
MJ
Wint
A
A
Wang
Z
Z
McIntyre
T M
TM
Albertine
K H
KH
Lane
R H
RH
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism* / Q000473:pathology; D006965:Hyperplasia / Q000473:pathology; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008171:Lung Diseases / Q000151:congenital / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology; D010743:Phospholipids / Q000378:metabolism; D010766:Phosphorylation; D010927:Placental Insufficiency / Q000378:metabolism*; D011247:Pregnancy; D011494:Protein Kinases / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D010743:Phospholipids; D016159:Tumor Suppressor Protein p53; D012694:Serine; D012313:RNA; D011494:Protein Kinases