Disordered enterocyte signaling and intestinal barrier dysfunction in the pathogenesis of necrotizing enterocolitis

David J. Hackam, Jeffrey S. Upperman, Anatoly Grishin, Henri R. Ford

Research output: Contribution to journalArticlepeer-review

Abstract

Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in neonates, and is characterized by the development of diffuse intestinal necrosis in the stressed, pre-term infant. Systemic stress causes a breakdown in the intestinal mucosal barrier, which leads to translocation of bacteria and endotoxin and the initiation of a signaling response within the enterocyte. This review summarizes recent evidence defining a clear role that defective enterocyte signaling plays in the pathogenesis of NEC through the following mechanisms: 1) The localized production of nitric oxide by villus enterocytes results in an increase in enterocyte apoptosis and impaired proliferation; 2) The translocation of endotoxin results in a PI3K-dependent activation of RhoA-GTPase within the enterocyte leading to decreased enterocyte migration and impaired restitution; 3) Dysregulated sodium-proton exchange within the enterocyte by endotoxin renders the enterocyte monolayer more susceptible to damage in the face of the acidic microenvironment characteristic of systemic sepsis; and 4) Endotoxin causes a p38-dependent release of the pro-inflammatory molecule COX-2 by the enterocyte, which potentiates the systemic inflammatory response. An understanding of the mechanisms by which disordered enterocyte signaling contributes to the pathogenesis of barrier failure and NEC--through these and other mechanims--may lead to the identification of novel therapeutic approaches for this devastating disease.

Original languageEnglish (US)
Pages (from-to)49-57
Number of pages9
JournalSeminars in pediatric surgery
Volume14
Issue number1
DOIs
StatePublished - 2005
Externally publishedYes

Keywords

  • Cox-2
  • Endotoxin
  • Enterocyte migration
  • Intestinal barrier function
  • Intestinal restitution
  • Nitric oxide
  • RhoA

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Surgery

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