van Veen Suzanne Q, Meijers Joost C M, Levi Marcel, van Gulik Thomas M, Boermeester Marja A
Department of Surgery, Surgical Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Shock. 2007 May;27(5):534-41. doi: 10.1097/01.shk.0000246897.27574.1b.
Peritonitis represents a procoagulant state because of activated coagulation and inhibited fibrinolysis. Intra-abdominal fibrin deposition-entrapping bacteria-prevents bacterial spread but impairs bacterial clearance. Activating intra-abdominal fibrinolysis by recombinant tissue-type plasminogen activator (r-tPA) early during peritonitis may enhance bacterial clearance and reduce inflammation. This study examines effects of abdominal r-tPA lavage on local and distant coagulation, fibrinolysis, and inflammatory responses in experimental polymicrobial peritonitis. Twenty-four hours after cecal ligation and puncture, mice were exposed to therapeutic abdominal lavage with varying doses of r-tPA or saline (controls). Coagulation, fibrinolysis, and inflammation were assessed in abdominal, systemic, and pulmonary compartments (n = 6 per group per time point). Survival was assessed during 96 h (n = 16 per group). Highest-dose (2 mg/mL) r-tPA lavage caused immediate death. High-dose (0.5 mg/mL) r-tPA lavage increased fibrinolysis, demonstrated by low abdominal plasminogen activator inhibitor 1 levels and elevated pulmonary tPA levels, resulting in reduced abdominal bacterial load, chemokine levels, leukocyte influx, and thrombin generation, along with less pulmonary fibrin depositions and organ damage on histological examination (P < 0.05 vs. saline lavage). Low-dose (0.05 mg/mL) r-tPA lavage showed hardly any effect compared with saline lavage. Adversely, abdominal and plasma interleukin (IL) 12 were elevated, whereas IL-10 levels were decreased after high-dose r-tPA lavage (P < 0.05 vs. saline). Survival rate was not affected by any dose of r-tPA lavage compared with saline lavage. Delayed local stimulation of fibrinolysis by peritoneal r-tPA lavage enhanced intra-abdominal bacterial clearance and reduced intra- and extra-abdominal coagulation responses in a dose-dependent manner. Survival rate was unaffected likely due to adverse changes in IL-12 and IL-10 levels.
由于凝血激活和纤维蛋白溶解受抑制，腹膜炎呈现促凝状态。腹腔内纤维蛋白沉积（包裹细菌）可防止细菌扩散，但会损害细菌清除。在腹膜炎早期通过重组组织型纤溶酶原激活剂（r-tPA）激活腹腔内纤维蛋白溶解可能会增强细菌清除并减轻炎症。本研究探讨腹腔内r-tPA灌洗对实验性多微生物腹膜炎局部和远处凝血、纤维蛋白溶解及炎症反应的影响。在盲肠结扎和穿刺24小时后，用不同剂量的r-tPA或生理盐水（对照组）对小鼠进行治疗性腹腔灌洗。在腹部、全身和肺部区域评估凝血、纤维蛋白溶解和炎症（每个时间点每组n = 6）。在96小时内评估生存率（每组n = 16）。最高剂量（2 mg/mL）的r-tPA灌洗导致立即死亡。高剂量（0.5 mg/mL）的r-tPA灌洗增加了纤维蛋白溶解，表现为腹部纤溶酶原激活物抑制剂1水平降低和肺部tPA水平升高，导致腹部细菌载量、趋化因子水平、白细胞流入和凝血酶生成减少，同时组织学检查显示肺部纤维蛋白沉积和器官损伤减轻（与生理盐水灌洗相比，P < 0.05）。低剂量（0.05 mg/mL）的r-tPA灌洗与生理盐水灌洗相比几乎没有任何效果。相反，高剂量r-tPA灌洗后腹部和血浆白细胞介素（IL）-12升高，而IL-10水平降低（与生理盐水相比，P < 0.05）。与生理盐水灌洗相比，任何剂量的r-tPA灌洗均未影响生存率。腹膜r-tPA灌洗延迟局部刺激纤维蛋白溶解以剂量依赖方式增强腹腔内细菌清除并减少腹腔内和腹腔外凝血反应。生存率未受影响可能是由于IL-12和IL-10水平的不利变化。
