SIMILAR CYTOKINE BUT DIFFERENT COAGULATION RESPONSES TO LIPOPOLYSACCHARIDE INJECTION IN D-GALACTOSAMINE-SENSITIZED VERSUS NONSENSITIZED RATS

To compare cytokine release and coagulation disturbances induced by ad ministration of high versus low doses of endotoxin (lipopolysaccharide [LPS]), we used two endotoxin test systems similar in mortality but d ifferent in the degree of endotoxemia. One group of rats (n = 11) rand omly received endotoxin (15.0 mg/kg of body weight intraperitoneally [ i.p.]) and 1 mi of Ringer's solution (nonsensitized animals). The seco nd group (n = 11) received 1 ml of D-galactosamine (500 mg/kg i.p.) an d endotoxin (100 mu g/kg i.p.) simultaneously (sensitized animals). En dotoxin levels in the plasma of nonsensitized rats were 1,000-fold hig her than those in the plasma of sensitized rats (69.33 x 10(3) +/- 22. 42 x 10(3) versus 75.8 +/- 27.08 ng of LPS per ml), leading to a morta lity of 91% in nonsensitized rats versus 82% in the sensitized-rat mod el within 48 h postendotoxemia. Serum transaminase activity increased up to 100-fold in sensitized rats as a Sign of hepatocyte damage. Desp ite the large difference in LPS levels in plasma, the time courses of the plasma tumor necrosis factor (TNF) increase were similar in the tw o groups, with a peak at 2 h (54 +/- 12 ng/ml in nonsensitized rats ve rsus 43 +/- 12 ng/ml in sensitized rats), and also similar to that of a group of nonsensitized rats (n = 5) that received a low dose of LPS (100 mu g/kg) only (52 +/- 21 ng/ml), while D-galactosamine alone did not induce TNF release. Despite similar TNF levels, a more pronounced coagulation disorder was observed at 4 h in nonsensitized rats (with t he high LPS dose) as measured by platelet counts, plasma fibrinogen le vels, and activated partial thromboplastin time prolongation (191 x 10 (3) +/- 107 x 10(3) cells per mu L, 40 +/- 24 mg/dl, and 53 +/- 15 s, respectively) than in rats with the low LPS dose either sensitized (49 5 x 10(3) +/- 153 x 10(3), 95 +/- 49, and 38 +/- 16, respectively) or nonsensitized (439 x 10(3) +/- 62 x 10(3), 170 +/- 18, and 35 +/- 11, respectively). From these data, we conclude that (i) TNF production in duced by LPS in rats is not changed by D galactosamine treatment; (ii) since endotoxin alone (100 mu g/kg of body weight) induced a TNF incr ease in nonsensitized rats similar to that seen in D-galactosamine-sen sitized rats but did not produce any lethality, the increased sensitiv ity to LPS in D-galactosamine-sensitized animals appears to be due to the higher level of sensitization of the animals to LPS-induced mediat ors; and (iii) similar cytokine responses to high and low doses of LPS (with or without D-galactosamine) but different coagulation disturban ces indicate that factors other than TNF also play a role in producing disseminated intravascular coagulation.