Data_Sheet_3_Meta-Analysis of Preclinical Studies of Fibrinolytic Therapy for Acute Lung Injury.docx

BackgroundAcute lung injury (ALI) is characterized by suppressed fibrinolytic activity in bronchoalveolar lavage fluid (BALF) attributed to elevated plasminogen activator inhibitor-1 (PAI-1). Restoring pulmonary fibrinolysis by delivering tissue-type plasminogen activator (tPA), urokinase plasminogen activator (uPA), and plasmin could be a promising approach.
ObjectivesTo systematically analyze the overall benefit of fibrinolytic therapy for ALI reported in preclinical studies.
MethodsWe searched PubMed, Embase, Web of Science, and CNKI Chinese databases, and analyzed data retrieved from 22 studies for the beneficial effects of fibrinolytics on animal models of ALI.
ResultsBoth large and small animals were used with five routes for delivering tPA, uPA, and plasmin. Fibrinolytics significantly increased the fibrinolytic activity both in the plasma and BALF. Fibrin degradation products in BALF had a net increase of 408.41 ng/ml vs controls (P < 0.00001). In addition, plasma thrombin–antithrombin complexes increased 1.59 ng/ml over controls (P = 0.0001). In sharp contrast, PAI-1 level in BALF decreased 21.44 ng/ml compared with controls (P < 0.00001). Arterial oxygen tension was improved by a net increase of 15.16 mmHg, while carbon dioxide pressure was significantly reduced (11.66 mmHg, P = 0.0001 vs controls). Additionally, fibrinolytics improved lung function and alleviated inflammation response: the lung wet/dry ratio was decreased 1.49 (P < 0.0001 vs controls), lung injury score was reduced 1.83 (P < 0.00001 vs controls), and BALF neutrophils were lesser (3 × 104/ml, P < 0.00001 vs controls). The mortality decreased significantly within defined study periods (6 h to 30 days for mortality), as the risk ratio of death was 0.2-fold of controls (P = 0.0008).
ConclusionWe conclude that fibrinolytic therapy may be effective pharmaceutic strategy for ALI in animal models.

背景：急性肺损伤（acute lung injury, ALI）以支气管肺泡灌洗液（bronchoalveolar lavage fluid, BALF）中纤溶活性受抑为特征，该现象由纤溶酶原激活物抑制剂-1（plasminogen activator inhibitor-1, PAI-1）水平升高所介导。通过递送组织型纤溶酶原激活物（tissue-type plasminogen activator, tPA）、尿激酶型纤溶酶原激活物（urokinase plasminogen activator, uPA）及纤溶酶以恢复肺部纤溶功能，是一种颇具前景的治疗策略。
目的：本研究旨在系统分析临床前研究中报道的纤溶治疗对急性肺损伤的整体获益情况。
方法：我们检索了PubMed、Embase、Web of Science及中国知网（CNKI）数据库，对纳入的22项研究中纤溶剂对急性肺损伤动物模型的有益效应数据进行分析。
结果：本研究使用大、小型动物模型，采用5种给药途径递送tPA、uPA及纤溶酶。纤溶剂可显著提升血浆及BALF中的纤溶活性。与对照组相比，BALF中的纤维蛋白降解产物净升高408.41 ng/ml（P<0.00001）。此外，血浆凝血酶-抗凝血酶复合物水平较对照组升高1.59 ng/ml（P=0.0001）。与之形成鲜明对比的是，BALF中的PAI-1水平较对照组降低21.44 ng/ml（P<0.00001）。动脉血氧分压净升高15.16 mmHg，同时二氧化碳分压显著降低（11.66 mmHg，与对照组相比P=0.0001）。此外，纤溶剂可改善肺功能并减轻炎症反应：肺湿/干重比值较对照组降低1.49（P<0.0001），肺损伤评分降低1.83（P<0.00001），BALF中的中性粒细胞数量显著减少（3×10^4/ml，P<0.00001 vs 对照组）。在预设的研究周期内（死亡率观察时间为6小时至30天），死亡率显著降低，死亡风险比为对照组的0.2倍（P=0.0008）。
结论：综上，在急性肺损伤动物模型中，纤溶治疗或是一种有效的药物治疗策略。