Naoki Hayase, Rohit R Chari, Alef A C Dos Santos, Yoshitaka Naito, Xuzhen Hu, Peter S T Yuen, Robert A Star
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引用次数: 0
Abstract
Background: Bolus antithrombin-III (AT) improved sepsis/organ dysfunction and survival in lipopolysaccharide/monomicrobial infusion pretreatment animal models; however, AT failed in clinical trials. Because insults and drug administration schedules differed between pre-clinical and clinical settings, we re-examined AT using a clinically relevant polymicrobial insult (cecal ligation and puncture, CLP) and a new method to continuously infuse AT after animals became ill.
Methods: Mice were catheterized with saline-filled osmotic minipumps. During CLP surgery we inserted AT- or saline-containing minipumps. We created and validated a ~ 6 h delay between sepsis induction and treatment. We compared delayed, continuous AT infusion with a conventional bolus AT injection using survival studies and 48 h studies.
Results: 6 h delayed, continuous AT infusion significantly improved 7d survival vs saline infusion (65% vs 29%, n = 21, p = 0.018) and vs a single injection of AT (65% vs. 19%, n = 21, p = 0.003). Delayed, continuous AT attenuated liver but not kidney or lung injury. Vascular leakage and inflammatory cytokines were suppressed only in liver. The highest accumulation of bacteria and thrombin at 48 h was in liver. AT did not change organ bacterial counts.
Conclusions: Delayed, continuous AT infusion improved 7d survival after CLP compared to single bolus AT injection or continuous vehicle. Liver may be critical in abdominal sepsis because of bacterial accumulation and subsequent thrombin generation. AT may be protective due to attenuation of thrombin-induced vascular leakage, inflammation, and liver injury during CLP sepsis. Because other organs were unprotected, AT may be combined with drugs protecting different organs.
背景：大剂量抗凝血素- iii （AT）可改善脂多糖/单微生物输注预处理动物模型的败血症/器官功能障碍和生存率；然而，AT在临床试验中失败了。由于临床前和临床设置的损伤和给药计划不同，我们使用临床相关的多微生物损伤（盲肠结扎和穿刺，CLP）和动物生病后持续输注AT的新方法重新检查AT。方法：小鼠用充盐微型渗透泵插管。在CLP手术中，我们插入了含AT或含盐的微型泵。我们创建并验证了脓毒症诱导和治疗之间约6小时的延迟。通过生存研究和48小时研究，我们比较了延迟、持续AT输注与常规AT大剂量注射。结果：延迟6 h，连续输注AT与生理盐水输注（65% vs 29%, n = 21, p = 0.018）和单次注射AT （65% vs 19%, n = 21, p = 0.003）相比，7d生存率显著提高。延迟的，持续的AT减轻肝脏，但没有肾或肺损伤。血管渗漏和炎症因子仅在肝脏受到抑制。48 h时细菌和凝血酶的积累量最高的是肝脏。AT未改变器官细菌计数。结论：与单次注射或连续注射相比，延迟、持续注射AT可提高CLP后7天的生存期。由于细菌积聚和随后凝血酶的产生，肝脏可能在腹部败血症中起关键作用。在CLP败血症中，AT可能由于凝血酶引起的血管渗漏、炎症和肝损伤的衰减而具有保护作用。由于其他器官不受保护，AT可能与保护不同器官的药物联合使用。
期刊介绍：
SHOCK®: Injury, Inflammation, and Sepsis: Laboratory and Clinical Approaches includes studies of novel therapeutic approaches, such as immunomodulation, gene therapy, nutrition, and others. The mission of the Journal is to foster and promote multidisciplinary studies, both experimental and clinical in nature, that critically examine the etiology, mechanisms and novel therapeutics of shock-related pathophysiological conditions. Its purpose is to excel as a vehicle for timely publication in the areas of basic and clinical studies of shock, trauma, sepsis, inflammation, ischemia, and related pathobiological states, with particular emphasis on the biologic mechanisms that determine the response to such injury. Making such information available will ultimately facilitate improved care of the traumatized or septic individual.
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