Abstract
Background & Aims: Experimental necrotizing enterocolitis (NEC) is characterized by circulating endotoxin (lipopolysaccharide [LPS]) and impaired enterocyte migration. We hypothesized that LPS increases integrin function and cell-matrix adhesion, leading to impaired enterocyte migration in the pathogenesis of NEC. Methods: NEC-like intestinal injury was induced in newborn rats by hypoxia/gavage feedings, and restitution was determined by assessing bromodeoxyuridine-labeled enterocytes along the crypt-villus axis. Newborn mice were injected with 5 mg/kg LPS. IEC-6 cells were treated with LPS ± LY294002 or wortmannin, and β1- and α3-integrins were assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunofluorescence. β1-integrin function was determined by adherence of fibronectin beads to IEC-6 monolayers. Migration of IEC-6 cells into a scraped wound was measured by time-lapse microscopy. Results: Newborn intestinal injury was associated with decreased intestinal restitution and increased α3- and β1-integrin expression in the ileal mucosa, which also was observed after LPS injection. In IEC-6 cells, LPS caused an increase in the expression of α3- and β1-integrins, a shift of β1-integrins from the cytoplasm to the plasma membrane and an increase in fibronectin bead adhesion during which β1-integrins accumulated underneath attached beads. These effects could be reversed with LY294002 or wortmannin, suggesting phosphatidylinositol- 3-phosphate kinase (PI3K) dependence. The increased integrin-matrix adhesion by LPS led to an inhibition of enterocyte migration, which could be reversed by anti-β1-antibodies. Conclusions: Enterocyte migration is inhibited by LPS through increased expression and function of α3- and β1-integrins. Modulation of enterocyte migration via integrins may provide novel insights into the pathogenesis of NEC, in which intestinal restitution is impaired.
Original language | English (US) |
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Pages (from-to) | 1012-1022 |
Number of pages | 11 |
Journal | Gastroenterology |
Volume | 128 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2005 |
Externally published | Yes |
ASJC Scopus subject areas
- Hepatology
- Gastroenterology