Leukotriene C4-induced radioprotection: the role of hypoxia.
Pretreatment of mice with leukotriene C4 (LTC4), a biological mediator that can cause marked contraction of vascular, tracheal, and bronchial smooth muscles, enhances radiation survival. Optimal protection is observed with 10 micrograms LTC4 per mouse (400 micrograms/kg body wt) administered subcutaneously 5 to 10 min prior to irradiation. Pretreatment with 10 micrograms LTC4 increases the LD50/30 from 8.36 Gy in mice receiving saline to 15.7 Gy, providing a dose reduction factor of 1.9. Enhanced survival of mice was observed with doses of 50 micrograms LTD4/mouse, but not with LTE4. Fifteen minutes after administration of 10 micrograms LTC4, the breathing rate is reduced by 33%, the blood paO2 by 20%, the paCO2 by 29%, and the HCO3- by 43%. Whole blood lactate increased by 288% at this same time. The period over which the elevation in blood lactate occurs is similar to the times for optimal radioprotection. These data coupled with the finding that protection was eliminated when irradiation occurred in an enriched oxygen atmosphere indicate that hypoxia plays a role in leukotriene C4-induced animal radiation survival. High-performance liquid chromatography and tissue distribution analyses support a role for an indirect mechanism since the highest levels of LTC4 in the tissues do not correlate with the peak time for radioprotection.