Effect of antileukocyte adhesion molecule antibodies, nitric oxide synthase inhibitor, and corticosteroids on endotoxin shock in mice

We compared the therapeutic effects of anti-leukocyte adhesion molecule antibodies (mAbs), a nitric oxide (NO) synthase inhibitor (monomethyl-l,-arginine, NMLA), and methylprednisolone (MP) on experimental endotoxin-induced shock in mice. Lipopolysaccharide (LPS, 30mg/kg) was administered to ICR mice intraperitoneally, While 1mg/kg mAb, 5–20 mg/kg NMLA, or 30mg/kg MP was administered intravenously. The placebo group received phosphate-buffered saline. The survival rate of the placebo group 48 h after LPS injection was 36%. The administration of anti-CD11a, anti-CD18, anti-lectin cell adhesion molecule-1 (anti-LECAM-1), and MP increased the survival rate to 70, 62, 64, and 100%, respectively; however, NMLA had no significant effect. A FACS analysis revealed that the CD18 expression of granulocytes increased 12-fold within 30 min after LPS administration. MP significantly suppressed its expression. The plasma level of nitrate/nitrite increased from 20 to 260 and 1000μM 4 and 16h, respectively, 20 mg/kg NMLA abolished NO production at 4h, while MP inhibited it for up to 16h. The hepatic malondialdehyde level increased from 0.50 to 2.46 nmol/mg protein at 4h. Administration of anti-CD18 and MP reduced the level to 1.80 and 1.41 nmol/mg protein, respectively, whereas NMLA did not affect it. The mAbs and MP were concluded to be useful agents for endotoxin shock. The abolition of NO production had little influence on the hepatic cellular injury associated with endotoxemia.