ADAPTIVE CYTOPROTECTION IN THE SMALL-INTESTINE - ROLE OF MUCUS

Gastric mucosal injury induced by strong irritants can be dramatically reduced by pretreating the mucosa with mild forms of the same irritan t. This phenomenon has been termed ''adaptive cytoprotection.'' The ai m of the present study was to use in vivo and in vitro approaches to s tudy adaptive cytoprotection in the small intestine using physiologica lly relevant concentrations of oleic acid. Anesthetized rats were inst rumented for perfusion of the proximal jejunum with 10 or 40 mM oleic acid (in 20 mM sodium taurocholate). Mucosal epithelial integrity was continuously monitored by measuring the blood-to-lumen clearance of Cr -51-labeled EDTA. Perfusion of the lumen with 40 mM oleic acid produce d a 10-fold increase in Cr-51-EDTA clearance, which was not affected b y a previous perfusion with 10 mM oleic acid, i.e., no adaptive cytopr otection. In another series of experiments, oleic acid was placed in t he lumen rather than perfused, and mucosal epithelial integrity was as sessed histologically. Intraluminal placement of 10 mM oleic acid resu lted in the generation of a mucus layer over the epithelium. Subsequen t placement of 40 mM oleic acid did not produce significant epithelial cell injury, i.e., adaptive cytoprotection. In in vitro studies, muci n (1, 5, and 10 mg/ml) was layered over confluent monolayers of Caco-2 cells prior to addition of 2 mM oleic acid in 4 mM sodium taurocholat e. The epithelial cell injury induced by oleic acid was inhibited by m ucin in a dose-dependent manner. Further studies indicate that mucin d oes not prevent, but simply delays, the onset of cell injury. Finally, mucin (in a dose-dependent manner) retarded the diffusion of [C-14]ol eic acid through an aqueous medium. Taken together, our findings sugge st that mucin secreted in response to an initial insult may contribute to adaptive cytoprotection in the small intestine by delaying access of oleic acid to mucosal epithelial cells.