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122 INTRAUTERINE GROWTH RESTRICTION AFFECTS INSULIN GROWTH FACTOR BINDING PROTEIN 3 BUT NOT INSULIN-LIKE GROWTH FACTOR 1 RECEPTOR EXPRESSION IN THE DEVELOPING RAT LUNG.
  1. R. F. Langen1,
  2. C. W. Callaway1,
  3. R. A. McKnight1,
  4. X. Yu1,
  5. R. H. Lane1
  1. 1Pediatrics, University of Utah, Salt Lake City, UT.

Abstract

Background Intrauterine growth restriction (IUGR) predisposes neonates toward chronic lung changes characterized by mesenchymal thickening. Insulin-like growth factor 1 (IGF-1) plays a crucial role in normal lung growth and development. Key modulators of IGF-1 activity include IGFBP-3 and IGF-1r. Previous studies have shown that IGFBP-3 binds IGF-1 and decreases its activity. In addition, evidence suggests that IGFBP-3 may exhibit growth inhibitory effects independent of its ability to down-regulate IGF-1 activity. Specifically, IGFBP-3 has been shown to inhibit the growth of fibroblasts derived from IGF-1r knockout mice. IGF-1r is a tyrosine kinase receptor that mediates the effects of IGF-1.

Objective We hypothesized that IUGR would decrease IGFBP-3 expression in the developing rat lung and thereby contribute to increased IGF-1 activity and mesenchymal thickening. Furthermore, we hypothesized that these changes would be independent of IGF-1r expression.

Design/Methods To prove these hypotheses, we used a rat model of IUGR induced through uteroplacental insufficiency. Lungs of control and IUGR rats (n = 6-8 litters per group) at day 0 and day 21 were harvested and flash frozen. We measured relative mRNA levels of IGFBP-3 and IGF-1r with RT-PCR at day 0 and day 21. We also measured IGFBP-3 protein levels in day 0 rats.

Results Significant results are expressed as percent of control ± SEM. IGF-1r mRNA levels were not different between IUGR and control rat lungs at either day 0 (p = .66) or day 21 (p = .32). While IGFBP-3 mRNA and protein levels did not differ at day 0 (p = .81 and .90, respectively), mRNA levels differed significantly by day 21 (40.1% ± 7.0%, p = .05).

Conclusions We conclude that IUGR decreases IGFBP-3 mRNA levels in the postnatal rat lung. IGF-1r expression is unaffected by IUGR. These results are particularly intriguing because although IUGR leads to mesenchymal thickening in the day 21 rat lung, we have previously demonstrated that IGF-1 mRNA expression in the postnatal IUGR rat lung is unchanged. We speculate that decreased IGFBP-3 during alveolarization results in increased IGF-1 bioavailability, which contributes to the mesenchymal thickening seen in the postnatal IUGR rat lung. This may be secondary to IUGR-induced imprinting on the IGFBP-3 gene that subsequently decreases its expression.

Supported by the CHRC.

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