Uchiba M, Okajima K, Murakami K
Department of Medicine, Kumamoto University School of Medicine, Japan.
Thromb Res. 1998 Mar 1;89(5):233-41. doi: 10.1016/s0049-3848(98)00012-7.
We previously demonstrated that antithrombin III reduced the injury to endothelial cells caused by activated leukocytes in rats administered endotoxin. This occurred via the increase of the endothelial release of prostaglandin I2, which is a potent inhibitor of leukocyte activation. We evaluated the dose of antithrombin III required to prevent such endothelial cell injury in rats administered endotoxin, by comparing the effects of various antithrombin II doses on the pulmonary vascular injury. The intravenous administration of endotoxin, 5 mg/kg, produced a transient accumulation of leukocytes in the lung, followed by pulmonary vascular injury, as indicated by an increase in the pulmonary vascular permeability, and coagulation abnormalities. The dose of 250 U/kg significantly inhibited all such effects of endotoxin. While lower doses of antithrombin III (50 and 100 U/kg) significantly inhibited such coagulation abnormalities, they failed to prevent either the pulmonary accumulation of leukocytes or the subsequent pulmonary vascular injury. Rats administered endotoxin exhibited an accumulation of neutrophils and edematous changes in the pulmonary interstitial space. Although such changes were reduced after 250 U/kg of antithrombin III, they were unaffected by lower doses of 50 and 100 U/kg. Plasma levels of 6-keto-PGF1alpha were markedly increased in rats 90 min after the administration of endotoxin, and were significantly decreased in the endotoxin-treated rats administered the lower doses of antithrombin III (50 and 100 U/kg), but not altered in those endotoxin-treated rats receiving 250 U/kg of antithrombin III. These findings suggest that a higher antithrombin III dose is necessary to prevent endothelial cell injury than is required to inhibit coagulation abnormalities in an animal model of sepsis. These observations support the notion that antithrombin III may prevent endotoxin-induced endothelial cell injury by promoting endothelial release of prostaglandin I2 and thus inhibiting leukocyte activation.
我们之前证明，在给予内毒素的大鼠中，抗凝血酶III可减轻活化白细胞对内皮细胞的损伤。这是通过增加内皮细胞释放前列腺素I2来实现的，前列腺素I2是白细胞活化的有效抑制剂。我们通过比较不同剂量抗凝血酶III对肺血管损伤的影响，评估了在给予内毒素的大鼠中预防此类内皮细胞损伤所需的抗凝血酶III剂量。静脉注射5mg/kg内毒素会使白细胞在肺中短暂积聚，随后出现肺血管损伤，表现为肺血管通透性增加和凝血异常。250U/kg的剂量可显著抑制内毒素的所有这些作用。虽然较低剂量的抗凝血酶III（50和100U/kg）可显著抑制此类凝血异常，但它们未能预防白细胞在肺中的积聚或随后的肺血管损伤。给予内毒素的大鼠在肺间质空间出现中性粒细胞积聚和水肿变化。虽然在给予250U/kg抗凝血酶III后这些变化有所减轻，但较低剂量的50和100U/kg对其没有影响。给予内毒素后90分钟，大鼠血浆中6-酮-前列腺素F1α水平显著升高，在给予较低剂量抗凝血酶III（50和100U/kg）的内毒素处理大鼠中显著降低，但在接受250U/kg抗凝血酶III的内毒素处理大鼠中未改变。这些发现表明，在脓毒症动物模型中，预防内皮细胞损伤所需的抗凝血酶III剂量高于抑制凝血异常所需的剂量。这些观察结果支持以下观点，即抗凝血酶III可能通过促进内皮细胞释放前列腺素I2从而抑制白细胞活化来预防内毒素诱导的内皮细胞损伤。
