Disordered enterocyte signaling and intestinal barrier dysfunction in the pathogenesis of necrotizing enterocolitis.
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.
Hackam
David J
DJ
Division of Pediatric Surgry, Children's Hospital of Pittsburgh, Pennsylvania 15217, USA.
Upperman
Jeffrey S
JS
Grishin
Anatoly
A
Ford
Henri R
HR
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
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