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Eur J Pediatr Surg 2012; 22(01): 097-104
DOI: 10.1055/s-0032-1306261
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Effects of Oxidative Stress on Intestinal Type I Insulin-Like Growth Factor Receptor Expression

N. Baregamian
1   Department of Surgery, University of Texas Medical Branch, Galveston, Texas, United States
,
J. Song
2   Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States
,
D. H. Chung
3   Department of Pediatric Surgery, Vanderbilt School of Medicine, Nashville, Tennessee, United States
› Author Affiliations
Further Information

Publication History

15 May 2011

21 September 2011

Publication Date:
20 March 2012 (online)

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Abstract

Introduction Oxidative stress activates multiple signaling transduction pathways, including the phosphatidylinositol 3-kinase (PI3-K), in an injured intestine as occurs in necrotizing enterocolitis (NEC). We have previously shown that hydrogen peroxide (H2O2)-induced PI3-K activation is significantly enhanced with exogenous insulin-like growth factor (IGF)-1 in intestinal epithelial cells. However, the effects of oxidative stress on IGF receptor type I (IGF-IR) activation and expression in the neonatal intestine during NEC are unknown.

Material and Methods Intestinal sections from neonates undergoing bowel resections (control = 3, NEC = 20) were analyzed for IGF-IR expression. NEC was induced in newborn mouse pups using hypoxia and hyperosmolar feeds, and distal small bowel segments were analyzed for IGF-IR expression (control = 3, NEC = 7). H2O2 was used to induce oxidative stress in rat (RIE-1) and fetal human (FHs74 Int) intestinal epithelial cells. Phosphorylation of IGF-IR, Akt, a downstream effector of PI3-K, and IGF-IR levels were determined by Western blotting. Flow cytometry, immunofluorescence, immunohistochemistry, IGF-IR tyrosine phosphorylation array, cell death enzyme-linked immunosorbent assay, and Western blotting were used to determine the IGF-IR expression.

Results An increased IGF-IR expression was noted in intestinal sections from NEC as well as murine model of NEC. H2O2 treatment rapidly activated IGF-IR and increased the expression in RIE-1 and FHs74 Int cells. Inhibition of IGF-IR resulted in significant RIE-1 cell apoptosis during oxidative stress. IGF-IR tyrosine phosphorylation array showed the recruitment of several key SH2 domain-containing proteins and oncogenes to the IGF-IR tyrosine kinase domain in H2O2-treated RIE-1 cells.

Conclusion IGF-IR-mediated activation of intracellular signaling may play a critical role during oxidative stress-induced apoptosis in NEC.

Keywords

phosphatidylinositol 3-kinase/Akt - insulin-like growth factor type I receptor - oxidative stress - intestinal injury
 

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