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

Abstract

Background: Acute 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.

Objectives: To systematically analyze the overall benefit of fibrinolytic therapy for ALI reported in preclinical studies.

Methods: We 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.

Results: Both 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).

Conclusion: We conclude that fibrinolytic therapy may be effective pharmaceutic strategy for ALI in animal models.

Keywords: fibrinolytic agents; interventions; lung diseases; molecular therapy; preclinical study.

Figure 1

Flow diagram of the literature search and selection.

Figure 2

Forest plot summarizing the effect of fibrinolytic therapy on overall mortality of acute lung injury animals. Squares and their sizes represent the risk ratio (RR) and corresponding contributions to overall effect (diamond), respectively. Horizontal lines through each square represent 95% confidence intervals (95% CI). I² depicts heterogeneity.

Figure 3

Effect of fibrinolytic therapy on PaO₂ (A) and PaCO₂ (B). Weighted mean difference (WMD, square) and overall effect (diamond) are depicted.

Figure 4

Effects of fibrinolytic treatment on the fibrinolysis in the plasma and bronchoalveolar lavage fluid (BALF). (A) Plasma plasminogen activator activity (PAA). (B) BALF PAA. (C) BALF fibrin degradation products (FDP). (D) BALF plasminogen activator inhibitor type 1 (PAI-1).

Figure 5

Effect of fibrinolytic therapy on plasma thrombin–antithrombin complexes.

Figure 6

Effects of fibrinolytic therapy on lung neutrophils (A), lung water content (B), and lung injury score (C).

Figure 7

Bias assessment of PaO₂ from 18 studies. (A) Funnel plots of precision (1/SE) as a function of weighted mean differences (WMD) showing the distribution of published study outcomes (filled circles). Vertical gray line is a global estimate of efficacy. (B) Egger regression of PaO₂ precision (1/SE) against WMD/SE.

Figure 8

Sensitivity analysis of PaO₂.