Activation of coagulation in C57BL/6 mice given verotoxin 2 (VT2) and the effect of co-administration of LPS with VT2

To obtain better insight into the pathogenesis of verotoxin-producing Esche richia coli-associated diseases, in this study, we explored the effect of v erotoxin 2 (VT2) on coagulation in an animal model. After being given VT2 ( 50 ng/kg, lethal dose), C57BL/6 mice showed progressively increasing expres sion of TF mRNA in the kidney and brain and elevated plasma levels of throm bin-antithrombin III complex (TAT), normotest, fibrinogen, and PAI-1 parall eling the disease course over 24 hours; platelet counts were decreased at 4 8 hours with hemorrhage in the kidney and brain. Go-administration of lipop olysaccharide (LPS, 0.5 mg/kg) with VT2 (50 ng/kg) exhibited more prominant and/or prolonged increase in not only expression of TF and PAI-1 mRNAs in the kidney and brain but also plasma levels of TAT, fibrinogen, and PAI-1 a nd was associated with more remarkable hemorrhage in the tissues. Although VT2 (5 ng/kg) was not a lethal dose, co-administration of LPS (0.5 mg/kg) w ith VT2 (5 ng/kg) enhanced the susceptibility to VT2, resulting in more pro longed elevation of TAT levels during the first 24 hours than that in the L PS group and a second elevation at 72 hours, followed by death. Plasma IL-1 beta level reached a maximum at 24 hours after VT2 (50 ng/ kg) injection p rior to the increase in TAT levels, whereas the increase in TNF alpha level immediately after injection was associated with the increase in PAI-1 mRNA . These observations indicate that the activation of coagulation by VT2 may occur through a mechanism different from that used by LPS, since plasma TA T levels rose in the mice immediately after LPS injection and returned to n ormal over 36 hours. (C) 2000 Elsevier Science Ltd. All rights reserved.