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 (H-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). Hwas 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. Htreatment 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 Htreated RIE-1 cells. Conclusion IGF-IR-mediated activation of intracellular signaling may play a critical role during oxidative stress-induced apoptosis in NEC.
Original language | English (US) |
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Pages (from-to) | 97-104 |
Number of pages | 8 |
Journal | European Journal of Pediatric Surgery |
Volume | 22 |
Issue number | 1 |
DOIs | |
State | Published - 2012 |
Externally published | Yes |
Keywords
- insulin-like growth factor type I receptor
- intestinal injury
- oxidative stress
- phosphatidylinositol 3-kinase/Akt
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health
- Surgery