Influence of short-term octreotide administration on chronic tissue injury, transforming growth factor beta (TGF-beta) overexpression, and collagen accumulation in irradiated rat intestine

The somatostatin analog octreotide was recently found to ameliorate radiati on-induced tissue injury in rat intestine. The present study addressed whet her octreotide reduces chronic intestinal radiation fibrosis, whether enter oprotection is conferred by direct or indirect mechanisms, and whether the effects are dose-dependent. Using a rat model designed for fractionated irr adiation, a segment of small intestine was sham-irradiated or exposed to 67 .2 Gy X-radiation in 16 daily fractions. Octreotide (0, 2, or 10 mg/kg/h) w as administered subcutaneously by osmotic minipumps for 4 weeks, from 2 day s before to 10 days after irradiation. Tissue injury was assessed at 2 week s (early phase) and 26 weeks (chronic phase) by quantitative histopathology and morphometry. Epithelial and smooth muscle cell proliferation was asses sed by proliferating cell nuclear antigen staining; connective tissue mast cell hyperplasia by metachromatic staining; and TGF-beta1 and collagen prot ein and mRNA by quantitative immunohistochemistry, in situ hybridization, a nd/or real-time fluorogenic probe reverse transcription-polymerase chain re action. Octreotide conferred dose-dependent protection against early (p = 0 .0003) and chronic (p < 0.0001) tissue injury. Octreotide abrogated radiati on-induced chronic increases in extracellular matrix-associated TGF-<beta> (p < 0.0001), collagen I (p = 0.0001), and collagen III (p = 0.0002) immuno reactivity. Octreotide did not affect radiation-induced changes in steady-s tate TGF-<beta>1 mRNA levels, mast cell hyperplasia, or smooth muscle cell proliferation. Octreotide reduced crypt epithelial cell proliferation (p = 0.01), but did not otherwise affect unirradiated intestine. Octreotide conf ers dose-dependent protection against delayed small bowel radiation toxicit y and ameliorates radiation fibrosis predominantly by reducing acute mucosa l injury. These data strengthen the rationale for using somatostatin analog s as enteroprotective agents in clinical radiation therapy.