Reduction of spontaneous and irradiation-induced apoptosis in small intestine of IGF-I transgenic mice

Abstract

Insulin-like growth factor I (IGF-I) may promote survival of putative stem cells in the small intestinal epithelium. Mitosis and apoptosis were quantified in crypts of nonirradiated and irradiated IGF-I transgenic (TG) and wild-type (WT) littermates. The mean apoptotic index was significantly greater in WT vs. TG littermates. After irradiation, apoptotic indexes increased, and WT mice showed a more dramatic increase in apoptosis than TG mice at the location of putative stem cells. After irradiation, no mitotic figures were observed in WT crypts, whereas mitosis was maintained within the jejunal epithelium of TG mice. The abundance and localization of Bax mRNA did not differ between nonirradiated littermates. However, there was more Bax mRNA in TG vs. WT mice after irradiation. Bax mRNA was located along the entire length of the irradiated crypt epithelium, but there was less Bax protein observed in the bottom third of TG mouse crypts compared with WT littermates. IGF-I regulates cell number by stimulating crypt cell proliferation and decreasing apoptosis preferentially within the stem cell compartment.

Prostaglandin E2 reduces radiation-induced epithelial apoptosis through a mechanism involving AKT activation and bax translocation

“…It is possible that the use of a larger test group in the earlier study would have resulted in a statistically significant difference between the Bax -/-and the WT mice after 8 Gy. Our finding of reduced apoptosis in irradiated Bax -/-mice is consistent with the work of Lund's group with IGF-1 transgenic mice (48). One target organ for IGF-1 is the small-intestinal epithelium, where it increases crypt cell proliferation and decreases bax expression.…”

Cell-specific effects of insulin receptor substrate-1 deficiency on normal and IGF-I-mediated colon growth

“…As found previously for small intestine (27), MT-hIGF transgene expression significantly increased crypt mitoses in colon of mice with two intact copies of the IRS-1 gene (Fig. 6).…”

“…The numbers of mitotic cells per crypt were assayed on 20 well-oriented crypts for each specimen by a single investigator who was unaware of the animal groupings. Apoptosis was assessed by morphological assays that have been verified to yield data equivalent to other methods such as terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling (27). Myocyte density in muscularis layers was assayed by counting nuclei per unit area (1,000 m 2 ) on hematoxylin and eosin-stained sections.…”

Recent advances in the management of radiation colitis

“…Administration of insulin-like g rowth factor (IGF)-I immediately following abdominal irradiation increases small-intestinal mass and improves indicators of mucosal integrity, suggesting acceleration of smallintestinal mucosal recovery from radiation injury [130] . More recently, growth hormone and IGF-I have been demonstrated to protect intestinal cells from radiationinduced apoptosis both in vitro, by inhibiting apoptosis of the cells and preserving the mucosal integrity [131] , and in vivo [132] , utilizing IGF-Ⅰ transgenic mice. Pancreatic enzymes can exacerbate acute intestinal radiation toxicity, and suppressing pancreatic secretion with synthetic somatostatin receptor analogs, such as octreotide, can reduce both early and delayed radiation colitis [133] .…”