Ridings P C, Blocher C R, Fisher B J, Fowler A A, Sugerman H J
Department of Surgery, Medical College of Virginia, Richmond 23298, USA.
J Trauma. 1995 Jul;39(1):81-8; discussion 88-9. doi: 10.1097/00005373-199507000-00011.
Activation of the kallikrein-kinin system in sepsis has long been recognized, but its role, beneficial or pathologic, has not been determined. Recently, however, specific bradykinin (BK) antagonists have become available and we sought to determine the effects of a BK antagonist, NPC17731, in a model of sepsis-induced acute lung injury (ALI).
Anesthetized swine were studied for 5 hours, receiving a 1-hour infusion of saline (Controls) or live Pseudomonas aeruginosa (Septic untreated). Treatment groups received a 5 mg/kg bolus of NPC17731 followed by a 1 mg/kg bolus hourly commencing either just before sepsis (Pretreatment) or 30 minutes following the onset of sepsis (Posttreatment).
Septic untreated animals showed a rapid, progressive decline in arterial PaO2 compared to controls, and this was significantly improved in both treatment groups. Bronchoalveolar lavage at 5 hours in both treatment groups also showed significant decreases in neutrophil (PMN) counts and protein content compared to untreated septic animals, indicating decreased PMN migration and alveolar-capillary membrane damage. Both treatment groups also showed reduced PMN sequestration in the lung compared to untreated animals, although PMNs did exhibit significant upregulation of PMN CD18 receptor expression and superoxide generation.
These data imply a significant role for BK in the pathogenesis of sepsis-induced ALI. Use of a competitive BK antagonist significantly attenuated the development of ALI without inhibiting PMN activation. BK antagonists may be a useful adjunct in the armamentarium against sepsis-induced ALI.
脓毒症中激肽释放酶 - 激肽系统的激活早已为人所知，但其作用，无论是有益的还是病理性的，尚未确定。然而，最近，特异性缓激肽（BK）拮抗剂已可获得，我们试图确定BK拮抗剂NPC17731在脓毒症诱导的急性肺损伤（ALI）模型中的作用。
对麻醉的猪进行5小时的研究，一组接受1小时的生理盐水输注（对照组），另一组接受活的铜绿假单胞菌（未治疗的脓毒症组）。治疗组在脓毒症发作前（预处理）或脓毒症发作后30分钟（后处理）开始，先静脉推注5mg/kg的NPC17731，随后每小时静脉推注1mg/kg。
与对照组相比，未治疗的脓毒症动物的动脉血氧分压（PaO2）迅速、逐渐下降，而两个治疗组的这一情况均有显著改善。与未治疗的脓毒症动物相比，两个治疗组在5小时时的支气管肺泡灌洗显示中性粒细胞（PMN）计数和蛋白质含量均显著降低，表明PMN迁移减少和肺泡 - 毛细血管膜损伤减轻。与未治疗的动物相比，两个治疗组肺内的PMN滞留也减少，尽管PMN确实表现出PMN CD18受体表达和超氧化物生成的显著上调。
这些数据表明BK在脓毒症诱导的ALI发病机制中起重要作用。使用竞争性BK拮抗剂可显著减轻ALI的发展，而不抑制PMN激活。BK拮抗剂可能是对抗脓毒症诱导的ALI的有用辅助药物。
