Antithrombin reduces leukocyte adhesion during chronic endotoxemia by modulation of the cyclooxygenase pathway
Antithrombin reduces leukocyte adhesion during chronic endotoxemia by modulation of the cyclooxygenase pathway
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DOI：
10.1152/ajpcell.2000.279.1.c98
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发表时间：
2000-07-01
影响因子：
5.5
通讯作者：
Menger, MD
中科院分区：
文献类型：
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作者：
Hoffmann, JN;Vollmar, B;Menger, MD
抗凝血酶 (AT) 被认为是凝血酶活性最重要的天然抑制剂，并已被证明可以改善脓毒症（内毒素）引起的多器官功能障碍过程中的独特临床参数。我们假设AT通过促进内皮细胞释放PGI(2)来抑制白细胞活化和微血管损伤，因此，我们研究了AT在内毒素血症期间对白细胞/内皮细胞相互作用和微血管灌注的影响。在叙利亚仓鼠的皮褶标本中，0 和 48 小时重复静脉内注射内毒素 [脂多糖 (LPS)，大肠杆菌，2 mg/kg] 诱发严重内毒素血症。 AT (250 IU/kg) 在 0、24 和 48 小时静脉内给药（n = 6，AT 组）。在对照动物（n = 5，对照）中，给予 LPS，但不补充 AT。通过活体荧光显微镜，在第一次 LPS 注射后 72 小时内分析白细胞-内皮细胞相互作用和功能性毛细血管密度（FCD；毛细血管灌注测量）。在第一次和第二次 LPS 注射后，AT 显着减弱了 LPS 诱导的小动脉和小静脉白细胞粘附 [P < 0.01，测量方差分析 (MANOVA)]。同时，在第一次和第二次 LPS 给药后，AT 可有效预防 LPS 诱导的 FCD 抑制（P，0.05，MANOVA）。通过用环氧合酶抑制剂吲哚美辛 (n 5 6) 进行预处理，AT 对白细胞粘附和 FCD 的影响被发现完全消除。因此，我们的研究表明，AT 可能通过从内皮细胞中释放前列环素来减少白细胞-内皮细胞相互作用和微血管灌注失败，从而在内毒素血症中发挥有益作用。
Antithrombin (AT) is known as the most important natural inhibitor of thrombin activity and has been shown to improve distinct clinical parameters during the course of septic (endotoxin)-induced multiple organ dysfunction. We hypothesized that AT acts by inhibiting leukocyte activation and microvascular injury via the promotion of endothelial release of PGI(2), and therefore, we studied the effects of AT on leukocyte/endothelial cell interaction and microvascular perfusion during endotoxemia. In a skinfold preparation of Syrian hamsters, severe endotoxemia was induced by repeated administration of endotoxin intravenously [lipopolysaccharide (LPS), Escherichia coli, 2 mg/kg] at 0 and 48 h. AT (250 IU/kg) was administered intravenously at 0, 24, and 48 h (n = 6, AT group). In control animals (n = 5, control), LPS was given without AT supplementation. By intravital fluorescence microscopy, leukocyte-endothelial cell interaction and functional capillary density (FCD; measure of capillary perfusion) were analyzed during a 72-h period after the first LPS injection. AT significantly attenuated LPS-induced arteriolar and venular leukocyte adherence after both the first and the second LPS injection [P < 0.01, measures analysis of variance (MANOVA)]. In parallel, AT was effective in preventing LPS-induced depression of FCD after the first and the second LPS administration (P, 0.05, MANOVA). By pretreatment with the cyclooxygenase inhibitor indomethacin (n 5 6), effects of AT on leukocyte adherence and FCD were found completely abolished. Thus our study indicates that AT exerts its beneficial effects in endotoxemia by reducing leukocyte-endothelial cell interaction and microvascular perfusion failure probably via liberation of prostacyclin from endothelial cells.