Association of leukopenia and intestinal permeability with radiation-induced sensitivity to endotoxin

Abstract

Sensitivity to the lethal effects of endotoxin is increased after exposure to ionizing radiation in the hematopoietic death range. We hypothesized that leukopenia and altered intestinal permeability may be causative factors for increased sensitivity to endotoxin after irradiation. The presence of leukocytes and platelets was correlated with sensitivity of male B6CBF1 mice to 0.25 mg of Salmonella typhosa endotoxin administered intraperitoneally. This study was conducted over the 10-day period following irradiation (1000 rads Co-60) and the beginning of deaths due to radiation alone. These data were then associated with the status of tight junction barriers (zonula occludens) between epithelial cells of the ileum. A biphasic pattern of sensitivity to endotoxin was observed in irradiated mice. Mice were resistant to endotoxin through day 2 after radiation, but sensitivity increased greatly (80% mortality) by day 3. Resistance increased by day 6 (6.7% mortality) and then dropped again by days 9 and 10 (100% mortality). Leukocyte numbers decreased 91% by day 2 (from 10,880 to 1,020 per mm 3) and further by day 3 (300 per mm 3). Leukopenia persisted through the duration of the experiment. Platelets began to decrease in number by day 5, and levels continued to drop until day 9. Disruption of some intestinal tight junctions was observed on days 1–5 after radiation. Junctional repair was evident by day 5. Repair was noted as extensive junctional elements on ablumenal membrane fracture faces. A combination of leukopenia and leakage of endotoxin from the intestine may account for increased sensitivity to endotoxin seen at day 3. Repair of the intestinal permeability barrier on day 5 coincided with reduced sensitivity to endotoxin. Later (7–10 days) bacteremia was present in host tissues, and mortality due to challenge with endotoxin was again increased. Disruption of some tight junctional barriers was seen again on days 9 and 10 after radiation.