Preclinical Studies Of Fibrinolytic Therapy For Acute Lung Injury:A Meta-Analysis

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.ObjectiveTo systematically analyze the efficacy and safety of fibrinolytic therapy for ALI reported in preclinical studies.MethodWe searched PubMed,Embase,Web of Science,and CNKI Chinese databases,and analyzed data retrieved from included studies for the beneficial effects of fibrinolytics on animal models of ALI.Evaluate the effectiveness and safety of different fibrinolytic on animal models of ALI using meta-analysis.The meta-analysis was performed using Stata12.0 and Review Manager 5.3.ResultA total of 22 studies were included by searching four databases.In the 22 animal experiments included:ALI model was constructed for both large animals(sheep,pig and dog)and small animals(mouse,rat and rabbit);the types of fibrinolytic drugs were tPA,uPA and plasmin.The route of administration of fibrinolytic drugs is intravenous,intraperitoneal,intratracheal,nebulized,and transgenic.1.Efficacy:Fibrinolytics significantly increased the fibrinolytic activity both in the plasma and BALF.Fibrin degradation products in BALF had a net increase of 408.41ng/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<0.00001vs controls),and BALF neutrophils were lesser(3×10~4/ml,P<0.00001 vs controls).2.Safety:The mortality decreased significantly within defined study periods(6 h to30 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.