Background: Early postnatal glucocorticoid exposure accelerates the maturation of the bowel mucosa but results in bowel wall thinning in the newborn mouse ileum and increases the risk of focal ileal perforation in extremely premature infants. We have previously demonstrated a redistribution of insulin-like growth factor-I (IGF-I) from the submucosa in control animals to the distal villi of those treated with early postnatal dexamethasone, implicating IGF-I as an important mediator of dexamethasone's capacity to alter tissue growth. To investigate the possibility that IGF binding proteins (IGFBPs) might contribute to this process, we characterized the localization and abundance of IGFBP peptides and mRNAs in the same model.
Methods: Newborn mice received daily intraperitoneal injections of dexamethasone (l μg/g) or phosphate-buffered saline and then were euthanized on day 3 of life. Their ileums were harvested and prepared for microscopy. Tissue sections of ileum from both treatment conditions were processed in parallel for immunolocalization of each of the six IGFBP peptides and for in situ hybridization of each of the six IGFBP transcripts.
Results: Transcripts for IGFBP-1, -2, and -3 were highly abundant and ubiquitous the ileal mucosa, whereas transcripts for IGFBP-4, -5, and -6 were less abundant in epithelial cells. There were no differences in abundance between control and dexamethasone-treated ileum with regard to mRNA localization or abundance for IGFBP-1, -2, -3, and -6. In contrast, mRNA transcripts for IGFBP-4 and -5 were modestly increased with dexamethasone treatment (although only IGFBP-4 was significant). Strikingly different patterns of IGFBP immunolocalization were observed between control and dexamethasone-treated animals. IGFBP-1, -2, -3, and -5 were not detected in control ileum, whereas IGFBP-4 and -6 were both present in the mucosa. In contrast, dexamethasone treatment resulted in dramatic mucosal increases in IGFBP-2, -3, -4, and -5, paralleling the changing distribution of IGF-I that we previously reported.
Conclusion: Taken together, these findings further implicate the IGF system as an important participant in dexamethasone-induced maturation in the newborn mouse ileum.
*Division of Neonatology, Department of Pediatrics, University of Virginia Health Sciences, Charlottesville, Virginia, U.S.A., and †Division of Neonatal–Perinatal Medicine, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Received October 29, 2001; accepted May 30, 2002.
Supported by grants no. HL1917l-18 SCOR (to A.D.S. and B.M.M.S.) and CHRCDA HD01421 (to P.V.G) from the National Institutes of Health, Bethesda, MD, and by start up funds from the Department of Pediatrics, University of Virginia Health Sciences, Charlottesville, VA.
Address correspondence and reprint requests to Dr. Phillip V. Gordon, Division of Neonatology, Department of Pediatrics, University of Virginia Health Sciences, Charlottesville, VA 22908–0386 (e-mail: email@example.com).