Abstract
Proinflammatory mediators such as histamine, platelet activating factor and nitric oxide increase intestinal epithelial permeability and lead to disrupt its barrier function. ChemicalIy induced increase in the epithelial permeability could be mediated by stimulation of the release of these mediators. Nevertheless, the contribution of each mediators appears to be difficult to elucidate in vivo. Hence, an in vitro evaluation methodology for detecting the potential contribution of the mediators to the enhancement in mucosal permeability due to absorption enhancers has been established. Permeability of the rat colonic epithelial membrane in the presence or absence of the adjuvants was determined in vitro with a modified Ussing-type diffusion chambers. Both histamine and its releaser compound 48/80 significantly increased the transepithelial permeability that monitored by using carboxyfluorescein as a poorly permeable maker. The increase in permeability was found to be inhibited by the in vivo treatment of the intestine with the intraperitoneal dose of diphenhydramine, a H1-blocker, or FPL-52694, a mast cell stabilizer, prior to the excision. The absorption enhancers, oleic acid, lauryl maltoside and sodium deoxycholate showed potent enhancement effects on the epithelial permeability. The enhanced permeability with sodium deoxycholate was found to be significantly suppressed by the H1-blocker, indicating that the enhancing effect of sodium deoxycholate was partially mediated by histamine released within the mucosa. On the other hand, the treatment with H1-blocker showed no effect on the mucosal permeability enhanced by oleic acid and lauryl maltoside. These results demonstrate that the methodology should be of potential usefulness in the evaluation of the possible contribution of inflammatory mediators to chemically induced hyperpermeability in intestinal mucosa especially by absorption enhancers. Investigation on the other inflammatory mediators is in progress.
