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Surgery. 2007 Aug;142(2):295-302.

Phosphatidylinositol 3-kinase pathway regulates hypoxia-inducible factor-1 to protect from intestinal injury during necrotizing enterocolitis.

Author information

1
Department of Surgery, The University of Texas Medical Branch, Galveston, Tex, USA.

Abstract

BACKGROUND:

Hypoxia is an important risk factor for development of necrotizing enterocolitis (NEC) in premature infants. Hypoxia-inducible factor (HIF)-1 is a transcription factor that plays a critical role in cellular responses to hypoxia and can be induced by phosphatidylinositol 3-kinase (PI3-K) pathway. Activation of the PI3-K and regulation of HIF-1 during NEC have not been elucidated.

METHODS:

NEC was induced in 3-day-old neonatal mice using hypoxia and artificial formula feedings. Mice were divided into 3 treatment groups: (1) NEC alone, (2) NEC with insulin-like growth factor (IGF)-I, or (3) NEC with Akt1 siRNA treatment. Animals were sacrificed, and intestinal sections were harvested for protein analysis, H&E, and immunohistochemical staining.

RESULTS:

In vivo model of NEC produced intestinal injury associated with increased protein expression of HIF-1alpha, pAkt, PARP, and caspase-3 cleavage. Pretreatment with IGF-1 attenuated an HIF-1alpha response. In contrast, targeted inhibition of Akt1 completely abolished NEC-induced expression of pAkt and upregulated HIF-1alpha activation.

CONCLUSIONS:

NEC activates important protective cellular responses to hypoxic injury such as HIF-1alpha and PI3-K/Akt in neonatal gut. Hypoxia-mediated activation of pro-survival signaling during NEC may be modulated with growth factors, which thus suggests a potential therapeutic option in the treatment of neonates with NEC.

PMID:
17689699
PMCID:
PMC2613757
DOI:
10.1016/j.surg.2007.04.018
[Indexed for MEDLINE]
Free PMC Article

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