The effect of total-body ionizing radiation on the digestive tract is dose-dependent and time-dependent. At low doses (1.5 Gy), one observes only a short prodromal syndrome consisting of nausea, vomiting, and gastric suppression. At doses greater than 6 Gy, the prodromal syndrome is more marked, and it is followed after a 2-5-day remission period by a subacute syndrome, characterized by diarrhea and hematochezia. This gastrointestinal syndrome is superimposed onto a radiation-induced bone marrow suppression. The combination of intestinal and hemopoietic syndromes results in dehydration, anemia, and infection, leading eventually to irreversible shock and death. The treatment of prodromal symptoms is based on the administration of antiemetics and gastrokinetics, although an effective treatment devoid of side effects is not yet available for human therapy. The treatment of the gastrointestinal subacute syndrome remains difficult and unsuccessful after exposure to total body doses greater than 8-10 Gy. Supportive therapy to prevent infection and dehydration may be effective if restoration or repopulation of the intestinal and bone marrow stem cells does occur. In addition, bone marrow transplantation may improve the prospect of treating the hemopoietic syndrome, although the experience gained in Chernobyl suggests that this treatment is difficult to apply in the case of nuclear accidents. Administration of radioprotectants before irradiation decreases damage to healthy cells, while not protecting cancerous tissues. In the future, stimulation of gastrointestinal and hemopoietic progenitor cells may be possible using cell growth regulators, but much remains to be done to improve the treatment of radiation damage to the gastrointestinal tract.

Administration of manganese or chromium chloride 1 h before challenge with a single bolus of Salmonella typhosa endotoxin completely obviated death in endotoxin-challenged mice.

Zinc chloride protected against lethality in mice undergoing endotoxin shock.

to clear endotoxin from the circulation and detoxify it in the liver of immunosuppressed animals. To determine if intestinal endotoxin may contribute to pathogenesis in immunosuppressed individuals, B6CBF1 mice were exposed to 850 rads X-rays, and transplanted with allogeneic CBA spleen cells. Aseptic endotoxemia, detected with the limulus lysate assay, was found at 24 and 72 hr postirradiation in livers of mice irradiated only. Contrary to this, endotoxin was not found in mice on days 5, 7, and 8 after X-irradiation. Mice died between 11 and 13 days after radiation exposure, at which time bacteria and endotoxin were detected in the liver. In contrast, endotoxin was demonstrable on days 1 and 5 in mice undergoing GVHD. Mice receiving allogeneic grafts after 850 rads survived only 7 days, while gram-negative organisms were detected frequently in liver fragments from 24 hr to day 7. By day 4, hepatosplenic localization of iv-injected [6ECr]endotoxin was reduced 50% in these animals and 2- to 3-fold increases in endotoxin levels were found in lung, kidney, heart, and brain. Hepatosplenic endotoxin concentration was not altered dramatically in mice receiving radiation alone. Endotoxin levels in other organs were not altered. Thus, endotoxin is present in detectable amounts in the liver of immunosuppressed mice.

Bacterial endotoxins increase nonspecific host resistance to a number of stresses. For example, resistance to radiation-induced damage is achieved through stimulation of granulocytic proliferation by endotoxin. Endotoxin is also a B-lymphocyte mitogen and thus has been used as an adjuvant for promoting resistance to antigens such as cancer cell implants. Repeated small doses of endotoxin, furthermore, can be used to establish a refractory state (tolerance) to further challenge with endotoxin. All of the resistance enhancing actions of endotoxin described above may contribute to the ability of endotoxin to increase resistance to bacterial infections. Experiments were designed to test the hypothesis that Salmonella typhosa endotoxin could be attenuated by treatment with ferric chloride (FeCl3) and that this preparation retained the biological activity of normal endotoxin. The authors found attenuated endotoxin to be as biologically active as untreated endotoxin, but it had the additional advantage of being relatively nontoxic. (GRA)

Endotoxin (lipopolysaccharide, LPS) treated with ferric chloride was tested for its potential as a non-toxic agent for enhancement of non-specific host resistance. A 1 mg dose of untreated endotoxin, injected i.p. into mice, resulted in 100 per cent mortality, whereas the same amount of chemically-treated endotoxin resulted in less than 35 per cent lethality. The radio-protective potential of the treated endotoxin was similar to that of untreated endotoxin, as 70 per cent of each group of mice tested with either substance survived a dose of 850 rad x-ray. Irradiated mice, challenged 8 days after 850 rad x-irradiation, died when injected with 25 mug of either untreated or treated endotoxin. Antibiotic decontamination of the intestinal tract of host animals reduced the possibility of toxicity from endogenous endotoxin after challenge. This treatment resulted in 100 per cent survival from a 25 mug challenge at 8 days post-irradiation. The ferric chloride-treated proved to be a more effective B-lymphocyte mitogen. At a dose of 100 mug, treated endotoxin resulted in a 50 per cent greater mitogenic stimulation of B-lymphocytes as compared with that found after exposure to untreated endotoxin. Several lines of evidence support the contention that tolerance to untreated endotoxin was induced by repeated injections of either endotoxin preparation 1) 100 per cent of all endotoxin-tolerant mice survived a 1 mg challenge dose of untreated endotoxin, 2) there was a reduced mitotic response of splenic B-lymphocytes after re-exposure with untreated endotoxin as compared with that observed for cells derived from saline-treated mice, and 3) all antibiotic decontaminated mice engrafted with spleen cells from mice made tolerant to either endotoxin preparation survive graft-versus-host disease. In conclusion, based on survival data from normal mice, ferric chloride-treated endotoxin is safer to use than normal endotoxin. Also, treated endotoxin can elicit biologic responses similar in magnitude to those found after injection of mice with untreated endotoxin.

: Elimination of enteric microflora by antibiotic treatment removes a source of endogenous infection in animals whose resistance has been compromised, but it may reduce resistance against exogenous infection. This possibility was evaluated in conventional and decontaminated normal mice and in those exposed to 850 rads x radiation or undergoing graft versus host disease (GVHD). When Salmonella typhimurium was perfused through mouse livers in situ approximately 70 percent of the organisms were trapped in hepatic sinusoids of normal and immunologically compromised animals. The trapping process was not affected by the absence of enteric flora. However, when bacteria were injected i.v. into mice, intestinal decontamination reduced bactericidal activity in normal and irradiated mice and in those undergoing GVHD. Approximately 50 percent of the injected S. typhimurium were killed in 20 min by conventional animals as opposed to the 25 percent killed by decontaminated animals. Reticuloendothelial uptake of 51Cr labeled bacterial endotoxin injected i.v. was reduced in animals receiving radiation or undergoing GVHD.