TRANSGENIC MICE THAT OVEREXPRESS THE HUMAN TREFOIL PEPTIDE PS2 HAVE AN INCREASED RESISTANCE TO INTESTINAL DAMAGE

pS2 is a member of the trefoil peptide family, all of which are overex pressed at sites of gastrointestinal injury, We hypothesized that they are important in stimulating mucosal repair. To test this idea, we ha ve produced a transgenic mice strain that expresses human pS2 (hpS2) s pecifically within the jejunum and examined the effect of this overexp ression on proliferation and susceptibility to indomethacin-induced da mage. A transgenic mouse was produced by microinjecting fertilized ooc ytes with a 1,7-kb construct consisting of rat intestinal fatty acid b inding protein promoter (positions -1178 to +28) linked to full-length (490 bp) hpS2 cDNA. Screening for positive animals was by Southern bl ot analysis. Distribution of hpS2 expression was determined by using N orthern and Western blot analyses and immunohistochemical staining. Pr oliferation of the intestinal mucosa was determined by assessing the c rypt cell production rate. Differences in susceptibility to intestinal damage were analyzed in animals that had received indomethacin (85 mg /kg s.c.) 0-30 h previously, Expression of hpS2 was limited to the ent erocytes of the villi within the jejunum. In the nondamaged intestine, villus height and crypt cell production rate were similar In transgen ic and negative (control) litter mates. However, there was a marked di fference in the amount of damage caused by indomethacin in control and transgenic animals in the jejunum (30% reduction in villus height in controls vs. 12% reduction in transgenic animals, P < 0.01) but the da mage sustained in the non-hpS2-expressing ileal region was similar in control and transgenic animals. These studies support the hypothesis t hat trefoil peptides are important In stimulating gastrointestinal rep air.