Abstract
We evaluated the mitigating effects of fibroblast growth factor 4 and 7 (FGF4 and FGF7, respectively) in comparison with long acting protected graft copolymer (PGC)-formulated FGF4 and 7 (PF4 and PF7, respectively) administered to C57BL/6J mice a day after exposure to LD50/30 (15.7 Gy) partial body irradiation (PBI) which targeted the gastrointestinal (GI) system. The PGC that we developed increased the bioavailability of FGF4 and FGF7 by 5- and 250-fold compared to without PGC, respectively, and also sustained a 24 hr presence in the blood after a single subcutaneous administration. The dose levels tested for mitigating effects on radiation injury were 3 mg/kg for the PF4 and PF7 and 1.5 mg each for their combination (PF4/7). Amifostine administered prior to PBI was used as a positive control. The PF4, PF7, or PF4/7 mitigated the radiation lethality in mice. The mitigating effect of PF4 and PF7 was similar to the positive control and PF7 was better than other mitigators tested. The plasma citrulline levels and hematology parameters were early markers of recovery and survival. GI permeability function appeared to be a late or full recovery indicator. The villus length and crypt number correlated with plasma citrulline level, indicating that it can act as a surrogate marker for these histology evaluations. The IL-18 concentrations in jejunum as early as day 4 and TPO levels in colon on day 10 following PBI showed statistically significant changes in irradiated versus non-irradiated mice which makes them potential biomarkers of radiation exposure. Other colon and jejunum cytokine levels are potentially useful but require larger numbers of samples than in the present study before their full utility can be realized.
Highlights
Treatments for radiation injury to the gastrointestinal (GI)-tract are desperately needed to ensure survival after exposure to ionizing radiation arising from an accident, nuclear warfare, or terrorist attacks using “dirty bombs”
We developed long acting formulations of FGF4 and FGF7 for subcutaneous use (PF4 and PF7, respectively) and evaluated their ability to increase survival when given 24 hours after partial body irradiation (PBI) injury; survival would likely be increased by accelerating growth and restoration of intestinal function, which are critical in stopping electrolyte loss, sepsis, inflammation, and lack of nutrition
The most efficient binder for FGF4 is p
Summary
Treatments for radiation injury to the gastrointestinal (GI)-tract are desperately needed to ensure survival after exposure to ionizing radiation arising from an accident, nuclear warfare, or terrorist attacks using “dirty bombs”. Long acting fibroblast growth factors and radiation injury mitigation the form of authors’ salaries and/or research materials
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