title: Disordered enterocyte signaling and intestinal barrier dysfunction in the pathogenesis of necrotizing enterocolitis.
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 mechanisms--may lead to the identification of novel therapeutic approaches for this devastating disease.
authors.affiliation: Division of Pediatric Surgry, Children's Hospital of Pittsburgh, Pennsylvania 15217, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hackam
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Upperman
authors.forename: Anatoly
authors.initials: A
authors.lastname: Grishin
authors.forename: Henri R
authors.initials: HR
authors.lastname: Ford
mesh_terms: D018988:Bacterial Translocation; D051546:Cyclooxygenase 2; D004731:Endotoxins / Q000494:pharmacology; D020345:Enterocolitis, Necrotizing / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D020895:Enterocytes / Q000502:physiology*; D006801:Humans; D007231:Infant, Newborn; D007413:Intestinal Mucosa / Q000473:pathology; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases