title: Phosphatidylinositol 3-kinase pathway regulates hypoxia-inducible factor-1 to protect from intestinal injury during necrotizing enterocolitis.
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.
authors: Department of Surgery, The University of Texas Medical Branch, Galveston, Tex, USA.
authors: Naira
authors: N
authors: Baregamian
authors: Piotr G
authors: PG
authors: Rychahou
authors: Hal K
authors: HK
authors: Hawkins
authors: B Mark
authors: BM
authors: Evers
authors: Dai H
authors: DH
authors: Chung
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D020345:Enterocolitis, Necrotizing / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D015996:Survival Rate; D015854:Up-Regulation / Q000502:physiology
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
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