Uchiba M, Okajima K, Murakami K, Okabe H, Takatsuki K
Department of Medicine, Kumamoto University Medical School, Japan.
Am J Physiol. 1996 Jun;270(6 Pt 1):L921-30. doi: 10.1152/ajplung.1996.270.6.L921.
We evaluated the effects of antithrombin III (AT III) on the pulmonary vascular injury induced by injecting rats with lipopolysaccharide (LPS) to investigate the possible usefulness of AT III as a treatment for acute respiratory distress syndrome. The intravenous administration of AT III prevented the pulmonary accumulation of leukocytes (as evaluated by myeloperoxidase activity) and the increase in pulmonary vascular permeability to 125I-bovine serum albumin induced by LPS. The increase in pulmonary vascular permeability induced by LPS administration was unaffected by various anticoagulants but was inhibited by the leukocytopenia induced by nitrogen mustard or by the administration of a granulocyte elastase inhibitor, ONO-5046. AT III given alone, but not heparin plus AT III or Trp49-modified AT III, which lacks affinity for heparin, significantly increased the plasma concentration of 6-keto-prostaglandin F1alpha, suggesting that the interaction of AT III with heparin-like substances at the endothelial cell surface promotes the release of prostacyclin from endothelial cells in vivo. Trp49-modified AT III failed to prevent the LPS-induced accumulation of leukocytes and vascular injury. The pulmonary accumulation of leukocytes and vascular injury induced by LPS were not prevented by administering AT III to rats that were pretreated with indomethacin. The continuous intravenous infusion of prostacyclin prevented the LPS-induced pulmonary accumulation of leukocytes and vascular injury. Findings suggest that AT III depends on its ability to promote the release of prostacyclin, a potent inhibitor of leukocyte activation, from endothelial cells to prevent pulmonary vascular injury induced by LPS.
我们评估了抗凝血酶III（AT III）对通过给大鼠注射脂多糖（LPS）诱导的肺血管损伤的影响，以研究AT III作为急性呼吸窘迫综合征治疗方法的潜在效用。静脉注射AT III可防止白细胞在肺内积聚（通过髓过氧化物酶活性评估）以及LPS诱导的肺血管对125I-牛血清白蛋白通透性的增加。LPS给药诱导的肺血管通透性增加不受各种抗凝剂的影响，但可被氮芥诱导的白细胞减少或粒细胞弹性蛋白酶抑制剂ONO-5046的给药所抑制。单独给予AT III可显著增加血浆6-酮-前列腺素F1α的浓度，但肝素加AT III或缺乏对肝素亲和力的Trp49修饰的AT III则不能，这表明AT III与内皮细胞表面肝素样物质的相互作用促进了体内内皮细胞释放前列环素。Trp49修饰的AT III未能预防LPS诱导的白细胞积聚和血管损伤。给用吲哚美辛预处理的大鼠注射AT III不能预防LPS诱导的白细胞在肺内积聚和血管损伤。持续静脉输注前列环素可预防LPS诱导的白细胞在肺内积聚和血管损伤。研究结果表明，AT III依赖于其促进内皮细胞释放前列环素（一种白细胞活化的有效抑制剂）的能力来预防LPS诱导的肺血管损伤。
