Meta-Analysis of Preclinical Studies of Fibrinolytic Therapy for Acute Lung Injury

• Main Authors: Cong Liu, Yana Ma, Zhenlei Su, Runzhen Zhao, Xiaoli Zhao, Hong-Guang Nie, Ping Xu, Lili Zhu, Mo Zhang, Xiumin Li, Xiaoju Zhang, Michael A. Matthay, Hong-Long Ji
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2018-08-01
• Series: Frontiers in Immunology
• Subjects: lung diseases; fibrinolytic agents; molecular therapy; interventions; preclinical study
• Online Access: https://www.frontiersin.org/article/10.3389/fimmu.2018.01898/full

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.