In Vivo Radioprotective Effects of Angiogenic Growth Factors on the Small Bowel of C3H Mice

Abstract

This study was undertaken to determine if acidic or basic fibroblast growth factor (FGF1 or FGF2) or vascular endothelial growth factor (VEGF) alters the radiation response of small bowel after total-body irradiation (TBI). Female C3H mice were treated with various doses of angiogenic growth factor administered intravenously 24 h before or 1 h after TBI. Radiation doses ranged from 7 to 18 Gy. End points measured were the number of crypts in three portions of the small bowel, the frequency of apoptosis of crypt cells at various times after TBI, and the LD50/30 (bone marrow syndrome) and LD50/6 (GI syndrome). Fibroblast growth factors alone, without TBI, decreased the number of crypts per circumference significantly. Among the factors tested, FGF2 caused the greatest decline in baseline crypt number. Despite this decrease in the baseline crypt number, after irradiation the number of surviving crypts was greater in animals treated with growth factor. The greatest radioprotection occurred at intermediate doses of growth factor (6 to 18 pg/mouse). Mice treated with FGF1 and FGF2 had crypt survival curves with a slope that was more shallow than that for saline-treated animals, indicating radiation resistance of crypt stem cells in FGF-treated mice. The LD50/6 was increased by approximately 10% for all treatments with angiogenic growth factors, whether given before or after TBI. Apoptosis of crypt cells was maximum at 4 to 8 h after TBI. The cumulative apoptosis was decreased significantly in animals treated with angiogenic growth factors, and the greatest protection against apoptosis was seen in animals treated with FGF2 prior to TBI. All three angiogenic growth factors tested were radioprotective in small bowel whether given 24 h before or 1 h after irradiation. The mechanism of protection is unlikely to involve proliferation of crypt stem cells, but probably does involve prevention of radiation-induced apoptosis or enhanced repair of DNA damage of crypt cells.

Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling

“…Disruption of the homeostatic balance between the host and microflora is now understood to be part of the pathogenesis of HIV infection and inflammatory bowel disease (4,5). Immune-based treatments for cancer, particularly those involving profound lymphodepletion, adoptive transfer of immune cells, or radiation have high potential to disrupt the host/microflora relationship and change it from mutualistic to pathogenic (6,7). As cancer immunotherapy develops, it is particularly important to understand the impact of these treatments on host/microbe homeostasis and the role of microorganisms in tumor immunity.…”

HST-1/FGF-4 plays a critical role in crypt cell survival and facilitates epithelial cell restitution and proliferation

“…Previous studies have shown that IL-1, SCF, KGF, FGF-1, FGF-2, and VEGF enhance the survival of irradiated murine intestinal crypt cells (Okunieff et al, 1988;Roberts et al, 1993;Leigh et al, 1995;Khan et al, 1997). Among them, FGF-1, FGF-2, and VEGF were reported to protect radiation-induced apoptosis of the crypt cells (Okunieff et al, 1988), and it was reported that the apoptosis of the crypt cells reached a sustained peak 4 h after irradiation and then declined back to baseline level within 24 h. In our whole-body irradiation regimen, HST-1/FGF-4 clearly suppressed the apoptotic event in crypt cells 4 h after irradiation, and also increased the survival of the crypt cells 3.5 days after irradiation.…”

“…Previous studies show that FGF-1, FGF-2, and VEGF protect radiation-induced apoptosis of the crypt cells (Okunieff et al, 1988). Next, we compared the level of radiation-induced apoptosis in vivo in the crypts of the small bowel at 4 h after the mice were given 9.0 Gy of whole-body irradiation (Figures 5a and 5b).…”

“…In recent years, several cytokines and growth factors that protect radiation-induced intestinal damage have been identified (Okunieff et al, 1988;Roberts et al, 1993;Leigh et al, 1995;Khan et al, 1997;Potten et al, 1997;Farrell et al, 1998;Cutler et al, 2003). Among them, we reported that fibroblast growth factor-4 (HST-1/FGF-4) protects mice from lethal irradiation by preventing bone marrow damage and intestinal tract damage (Takahama et al, 1999).…”

Circulating basic fibroblast growth factor declines during Cy/TBI bone marrow transplantation

“…[7][8][9][10][11][12][13] bFGF and other members of the FGF family of proteins have been shown to radioprotect the small bowel epithelium. 14,15 bFGF has been shown to radioprotect haematopoietic progenitors with particularly beneficial effects on megakaryopoiesis and erythropoiesis, 3 and bFGF also appears to prevent pulmonary and vascular toxicity by reducing apoptosis of endothelium. 16,17 bFGF has been shown to alleviate bone growth retardation in juvenile mice, even when given a month or more after irradiation.…”