I

Figure 4. Effect of RD-LPS or LPS pretreatraent in rats on plasma nitrate/nitrite levels (A), peritoneal macrophage (Mr) nitrate/nitrite levels (B) and lung iNOS activity (C) after subsequent endotoxin challenge. Rats, given sublethal doses of RD-t.PS, LP® (1 ing/kg i,p.) or saline solution only (control) Tor Tour days, were challenged with a high dose od.PS (15 nig/kg i.p.) on the fifth day. Open columns represent basal values before lethal LPS challenge; filled columns represent values obtained 6 h a ller high-dose l.PS challenge. Fach value represents the mean ± SRM of five rats for each group, !,P<0.01 versus control, # P < 0.O1 versus LPS pretreatment.

7. THO EFFECT OF RD-LPS ON NITRIC OXIDE (NO) PRODUCTION

During the study of pro-inflammatory mediators the importance of nitric oxide (NO) has been recognised. NO plays an important role in endotoxin-induced circulatory and metabolic alterations. LPS stimulates the production of the inductive NO synthase enzyme (iNOS) in various cell types. This mechanism contributes to LPS toxicity. For this reason we have examined the effect of LPS and RD-LPS on the NO system. LPS-trcated (10 ng/ml) macrophages (J774 cell line) produced iNOS, which resulted in increased NO production. If, however, the cells were pretreated 24 hours earlier with RD-LPS (10 ng/ml), no NO response was detected after the subsequent LPS treatment. In contrast, when the cells were pretreated with LPS, no change was observed in the NO response to subsequent LPS challenge. The treatment of rats with repeated LPS injections (I mg/kg/day ip. for 4 days) prevented the rise of nitrate/nitrite levels in the blood. These results indicate that RD-LPS induced tolerance towards NO induction by toxic LPS [46] (Figs. 3 and 4).

8. RD-LPS INCREASES NATURAL RESISTANCE, PROTECTS AGAINST VARIOUS FORMS OF SHOCK, AND EXERTS ADJUVANT AND ANTITUMOUR EFFECTS. POSSIBLE MECHANISMS OF ACTION.

8.1. Endotoxin shock

It is well known that an adequate dose of endotoxin is capable of inducing severe shock [47,48]. This phenomenon is readily induced in sensitive animals simply by LPS injection into the bloodstream or into the peritoneal cavity. We demonstrated that RD-LPS pretreatment of rats, mice, hamsters, guinea pigs, dogs, piglets, horses and monkeys was capable of inducing full endotoxin tolerance. Tolerance will develop within 24 hours and will disappear between 1 and 4 weeks. The protective effect of RD-LPS was further supported by the measurement of circulatory parameters. LPS caused major alterations in blood pressure and cardiac output. Pretreatment with RD-LPS moderated, or fully protected against, the haemodynamic effects of toxic LPS L49J.

8.2. Peritonitis caused by intestinal bacteria and septic shock

The prevention of peritonitis due to faecal bacteria and of sepsis is important in clinical practice. Therefore, we studied the effect of RD-LPS in experimental models of these conditions. It was shown that pre-treatment with RD-LPS protected 90% of the animals against lethal peritonitis or septic shock [9,47,50]. Other investigators confirmed these results [51]. It is indicated that RD-LPS may be used prior to abdominal surgery for the elevation of natural resistance [7,9,52],

8.3. Haemorrhagic shock

Haemorrhagic shock is a significant problem in surgery. Fine and co-workers [53] presumed several years ago that endotoxaemia plays a role in the pathology of this condition. For this reason we studied the effect of RD-LPS on haemorrhagic shock and demonstrated that the pretreatment of dogs resulted in survival of the majority (70%) of the animals affected by lethal shock [47,49,54],

8.4. Intestinal ischaemic shock

The occlusion of the superior mesenteric artery (arteria mesenterica superior or cranialis) leads to severe intestinal ischaemia in man, which frequently results in death even when the occlusion is successfully removed by surgery. In animals the experimental intestinal ischaemia induced by temporary closure of the superior mesenteric artery is an excellent model for the examination of that injury. It has been demonstrated earlier that LPS absorbed from the gut during reperfusion plays an important role in the pathogenesis of this condition [48,53,55-57]. We studied the effect of RD-LPS in experimental intestinal ischaemia and showed that the majority of rats (70%) were saved from lethal intestinal ischaemic injury by our preparation [9,48].

8.5. Pulmonary shock

This condition is of clinical importance and bacterial endotoxins play an important role in its pathogenesis. In animal model systems LPS is used for induction, which evokes a characteris-

Table II Protection by radiodetoxified endotoxin (RD-LPS) against various forms of experimental shock, radiation disease and infections.

Experimental intervention /[species]

Protective value [%]

Endotoxin shock [LPS, rat, pig]

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