Somatostatin analogue predisposes enterocytes to apoptosis

The somatostatin analogue octreotide impairs intestinal regeneration and the adaptive response to intestinal resection and other stimuli. These effects are mediated in part by inhibition of enterocyte migration and proliferation. The aim of this study was to determine whether octreotide promotes enterocyte apoptosis. Twenty-four New Zealand white rabbits were studied including 18 animals that underwent patch enteroplasty in the distal ileum to stimulate the mucosa and six unoperated controls. The patched animals either received 100 microgram or 1000 microgram of subcutaneous octreotide daily or served as operated control subjects. Normal ileal mucosa adjacent to the patch was evaluated at 7 days for villus height, crypt depth, crypt cell production rate (CCPR), and in situ end labeling of DNA fragmentation. Mean DNA fragmentation was significantly greater in octreotide-treated animals (P <0.05 Mann-Whitney rank test). Fragmentation scores ranged from 1.0 to 1.5 in controls and 1.1 to 2. 65 in treated animals. Staining of enterocytes was quite heterogenous, however, among the villi of individual treated animals. Staining was greater and cells with chromatin condensation were more prevalent near the tip of the villus. Octreotide increased apoptosis at the villus tip, lateral villus, and crypt. The two control groups had similar villus height, crypt depth, and CCPR The two octreotide-treated groups had similar villus height and CCPR compared to control animals. However, crypt depth was significantly less in the octreotide-treated animals (100 +/- 9 micrometer and 90 +/- 6 micrometer, 100 microgram, and 1000 microgram) compared to controls (121 +/- 10 micrometer and 117 +/- 10 micrometer, unoperated and operated; P <0.05). Crypt depth but not villus height correlated with DNA fragmentation. Neither correlated with CCPR. The following conclusions were reached: (1) Octreotide treatment is associated with increased DNA fragmentation in enterocytes; (2) octreotide promotes apoptosis in both villus and crypt compartments; (3) predisposition to apoptosis may play a role in octreotides effects on intestinal regeneration and adaptation; and (4) the role of proliferation and apoptosis in determining the size of the enterocyte compartments remains unclear.