Prednisolone inhibits endotoxin-induced disseminated intravascular coagulation and improves mortality in rats: importance of inflammatory cytokine suppression.
In order to determine whether prednisolone has a protective effect against the development of disseminated intravascular coagulation (DIC), we measured the effect of prednisolone on changes in hemostatic parameters and plasma levels of inflammatory cytokines in endotoxin-treated rats. Decreases in platelet count and fibrinogen levels, prolongation of prothrombin time, and increases in the plasma fibrin degradation products and levels of thrombin-antithrombin III (TAT) complex following the administration of endotoxin, all of which are associated with DIC, were significantly suppressed by the administration of prednisolone. Heparin administration significantly suppressed changes in all these parameters except for the decrease in platelet count. The combination of prednisolone and heparin was more effective than either treatment alone. In order to determine whether these effects of prednisolone are correlated with the suppression of inflammatory cytokine production, we examined the relationship between changes in plasma levels of cytokine, the hemostatic parameters listed above, and mortality using a number of intervention regimens designed to alter events of the experimentally induced DIC. Changes in hemostatic parameters associated with DIC following 30 mg/kg per 4 h of endotoxin infusion were significantly suppressed by treatment with 1 mg/kg prednisolone 30 min before beginning endotoxin infusion, followed by administration of 250 U/kg heparin 2 h after the start of endotoxin infusion (prednisolone-endotoxin-heparin regimen). The heparin and prednisolone were administrated subcutaneously. The administration of prednisolone and heparin in the reverse order (i.e. heparin first and prednisolone second: heparin-endotoxin-prednisolone regimen) also suppressed changes in hemostatic parameters, albeit to a smaller degree. Cytokine production was also significantly suppressed by the first treatment, but was not affected by the regimen in which heparin was administered first. Administration of prednisolone alone or heparin alone 30 min before endotoxin significantly reduced the number of renal glomeruli with fibrin thrombi. Plasma levels of creatinine and alanine transferase were reduced only by prednisolone. Increased plasma levels of interleukin-1beta, tissue necrosis factor-alpha and interleukin-6 were suppressed by prednisolone but not by heparin, and there were significant correlations between plasma levels of TAT and cytokines. Prednisolone was more effective than heparin in reducing mortality at 24 h after 100 mg/kg over 4 h of endotoxin infusion (four of 20 versus 15 of 20 deaths for prednisolone and heparin, respectively). These findings suggest that prednisolone inhibits the development of endotoxin-induced DIC and reduces mortality by a different mechanism than heparin, possibly through suppressing the production of inflammatory cytokines. Prednisolone may be efficacious in preventing DIC and multiple organ dysfunction caused by endotoxin.
Yamazaki
M
M
Third Department of Internal Medicine, Kanazawa University School of Medicine, Japan. myamazaki@med3.m.kanazawa-u.ac.jp
Aoshima
K
K
Mizutani
T
T
Ontachi
Y
Y
Saito
M
M
Morishita
E
E
Asakura
H
H
Matsuda
T
T
Triplett
D A
DA
D000818:Animals; D000990:Antithrombin III / Q000032:analysis; D001777:Blood Coagulation; D001778:Blood Coagulation Disorders / Q000139:chemically induced / Q000401:mortality / Q000517:prevention & control*; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood / Q000187:drug effects; D004211:Disseminated Intravascular Coagulation / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000009:adverse effects* / Q000494:pharmacology; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005340:Fibrinogen / Q000032:analysis; D006487:Hemostasis; D006493:Heparin / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000293:injuries; D008297:Male; D010447:Peptide Hydrolases / Q000032:analysis; D010976:Platelet Count; D011239:Prednisolone / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015996:Survival Rate; D013997:Time Factors
D018925:Chemokines; D016207:Cytokines; D004731:Endotoxins; D005338:Fibrin Fibrinogen Degradation Products; C046193:antithrombin III-protease complex; C036309:fibrin fragment D; D000990:Antithrombin III; D005340:Fibrinogen; D006493:Heparin; D011239:Prednisolone; D010447:Peptide Hydrolases