Department of Pediatrics, Fukushima Medical University School of Medicine, Fukushima City, Fukushima, Japan.
Nephrol Dial Transplant. 2015 Jun;30(6):969-77. doi: 10.1093/ndt/gfv004. Epub 2015 Feb 17.
Recombinant human soluble thrombomodulin (rhTM) is a promising therapeutic natural anticoagulant that is comparable to antithrombin, tissue factor pathway inhibitor and activated protein C. In order to clarify the efficacy of rhTM for the treatment of typical hemolytic uremic syndrome (t-HUS), we examined changes in renal damage in t-HUS mice treated with rhTM or vehicle alone.
We used severe and moderate t-HUS mice injected with shiga toxin (Stx) and lipopolysaccharide (LPS). The severe t-HUS mice were divided into two subgroups [an rhTM subgroup (Group A) and a saline subgroup (Group B)] along with the moderate t-HUS mice [an rhTM subgroup (Group C) and a saline subgroup (Group D)]. Groups E and F were healthy mice treated with rhTM or saline, respectively.
All mice in Group B died at 80-90 h post-administration of Stx2 and LPS whereas all mice in Group A remained alive. Loss of body weight, serum creatinine level, endothelial injury and mesangiolysis scores at 24 h after administration in the t-HUS mice treated with rhTM were lower than those in t-HUS mice treated with saline. The levels of hemoglobin at 6 h and platelet counts at 24 h after administration in Group A were higher than those in Group B. Serum interleukin (IL)-6, IL-1β and tumor necrotic factor (TNF)-α levels at 24 h after administration in Group A were lower than those in Group B. Serum C5b-9 levels at 24 h after the administration and serum fibrinogen degradation product (FDP) at 72 h after the administration of Stx2 and LPS were lower in Group A than in Group B.
These results indicate that rhTM might afford an efficacious treatment for t-HUS model mice via the inhibition of further thrombin formation and amelioration of hypercoagulant status.
重组人可溶性血栓调节蛋白（rhTM）是一种有前途的治疗性天然抗凝剂，可与抗凝血酶、组织因子途径抑制剂和活化蛋白 C 相媲美。为了阐明 rhTM 治疗典型溶血尿毒症综合征（t-HUS）的疗效，我们研究了 rhTM 或单独载体治疗的 t-HUS 小鼠肾脏损伤的变化。
我们使用注射志贺毒素（Stx）和脂多糖（LPS）的严重和中度 t-HUS 小鼠。严重 t-HUS 小鼠分为两组[rhTM 亚组（A 组）和生理盐水亚组（B 组）]，以及中度 t-HUS 小鼠[rhTM 亚组（C 组）和生理盐水亚组（D 组）]。E 组和 F 组分别为用 rhTM 或生理盐水治疗的健康小鼠。
Stx2 和 LPS 给药后 80-90 小时，B 组所有小鼠死亡，而 A 组所有小鼠均存活。与生理盐水治疗的 t-HUS 小鼠相比，rhTM 治疗的 t-HUS 小鼠给药后 24 小时体重减轻、血清肌酐水平、内皮损伤和系膜溶解评分降低。给药后 6 小时 A 组血红蛋白水平和 24 小时血小板计数高于 B 组。给药后 24 小时 A 组血清白细胞介素（IL）-6、IL-1β和肿瘤坏死因子（TNF）-α水平低于 B 组。给药后 24 小时 A 组血清 C5b-9 水平和 Stx2 和 LPS 给药后 72 小时血清纤维蛋白原降解产物（FDP）水平低于 B 组。
这些结果表明，rhTM 通过抑制进一步的凝血酶形成和改善高凝状态，可能为 t-HUS 模型小鼠提供有效的治疗。
