Background. Gastrointestinal mucosa heals by restitution and proliferation. These are difficult to distinguish in vivo. Methods. Human Caco-2 enterocytes were cultured on matrix proteins (collagen I, laminm, fibronectin) with growth factors (epidermal growth factor [EGF] and transforming growth factor-β1 [TGF-β1]) and the tyrosine kinase and prostaglandin inhibitors genistein and indomethacin. Healing was modeled by means of monolayer expansion, proliferation by means of 3H-thymidine uptake, and restitution by means of mitomycin-blocked migration. Results. Changing matrix composition failed to alter proliferation, but collagen I stimulated migration more than laminin or fibronectin (laminin/collagen, 68% ± 2%; p < 0.05). EGF (30 ng/ml) increased proliferation on both collagen (225% ± 11% of basal) and laminin (206% ± 26%) but increased migration only over laminin (210% ± 17%) (all, p < 0.05). TGF-β1, (200 pg/ml) stimulated migration over laminin (187% ± 18%, p < 0.005) but inhibited migration over collagen (89% ± 3%, p < 0.01) and did not affect 3H-thymidine uptake. When cultured on laminin, EGF but not TGF-β1 altered organization of the α2 integrin subunit. Genistein (100 μmol/L) inhibited basal and EGF-stimulated 3H-thymidine uptake. In addition, it prevented EGF stimulation of replication-blocked migration (81% ± 10% vs 190% ± 20% of basal, p < 0.0001) without altering basal replication-blocked migration. Indomethacin (10-5 mol/L) did not alter migration but inhibited basal and EGF-stimulated proliferation by 7% ± 1% (each, p < 0.005). Conclusions. Restitution and proliferation appear independently regulated by matrix and growth factors. It may be possible to individually target specific phases of mucosal healing by means of pharmacologic agents.
|Original language||English (US)|
|Number of pages||10|
|State||Published - Aug 1992|
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