Relationship between loss of rat colonic surface epithelium induced by deoxycholate and initiation of the subsequent proliferative response.

Bile acids increase the proliferative activity of rat colonic epithelium. However, the mechanisms responsible are unknown. The present study examined the relationships between deoxycholate (DOC) induced surface cell sloughing, as measured by loss of DNA into the lumen and by light microscopy, and the subsequent increases in mucosal ornithine decarboxylase activity and [3H]thymidine (dThd) incorporation into mucosal DNA induced by deoxycholate. Intracolonic instillation of DOC (10 mumol; 5 mM) resulted in a progressive increase in luminal DNA content which was significant by 1 min and maximal by 1 h. No further increase in luminal DNA occurred between 1 and 4 h after DOC. Similarly, light microscopy demonstrated a progressive loss of surface epithelium between 10 min and 1 h after DOC instillation. By 4 h after DOC, the colonic mucosal surface was normal histologically. The rapid repair of the epithelial surface occurred without a detectable increase in [3H]dThd incorporation into DNA within 4 h. The latter finding thus suggested that upward migration of nondividing crypt epithelial cells rather than the rapid initiation of new DNA synthesis and new mitotic activity was responsible for surface repair. Enhanced proliferative activity of colonic mucosa, as measured by increased [3H]dThd incorporation into DNA, did occur subsequently (12 to 24 h) after instillation of DOC. The dose response of early surface cell loss and the subsequent proliferative response to DOC were identical, consistent with a link between these two DOC mediated events. However, two observations suggested that surface epithelial loss alone was not sufficient to trigger the proliferative response to DOC: intracolonic instillation of DOC followed by removal of the DOC solution at 1 h, at which time surface epithelial loss was maximal, did not result in an increase in ornithine decarboxylase activity or [3H]dThd incorporation into DNA when these parameters were assessed at 4 h or 12 to 48 h, respectively; phenidone, an antioxidant and radical scavenger, and bis[(3,5-diisopropyl-salicylato) (O,O) copper(II), a lipophilic agent with superoxide dismutase activity, abolished the DOC mediated proliferative response but did not prevent the early loss of surface cells. The results imply that events other than or in addition to surface cell loss are necessary for the expression of the action of DOC to stimulate the proliferative activity of colonic epithelium.