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

This year is the 50th anniversary of the first description of acute respiratory distress syndrome (ARDS). Since then, much has been learned about the pathogenesis of lung injury in ARDS, with an emphasis on the mechanisms of injury to the lung endothelium and the alveolar epithelium. In terms of treatment, major progress has been made in reducing mortality from ARDS with lung-protective ventilation, using a tidal volume of 6 mL per kg of predicted bodyweight and a plateau airway pressure of less than 30 cm H2O. In more severely hypoxaemic patients with ARDS, neuromuscular blockade and prone positioning have further reduced mortality, probably by extending the therapeutic effects of lung protective ventilation. Fluid-conservative therapy has also increased ventilator-free days in patients with ARDS. The lack of success of pharmacological therapies for ARDS, however, presents a continued challenge in the field. In addition to presenting a brief summary of previous experience with clinical trials in ARDS, we focus in this Review on future opportunities to improve clinical trial design to maximise the likelihood of identifying beneficial pharmacological therapies. In view of the heterogeneity in ARDS, both prognostic and predictive enrichment strategies are needed that target therapies toward specific subgroups of patients with ARDS on the basis of both severity and biology. Approaches to reducing heterogeneity in ARDS clinical trials include using physiological, radiographic, and biological criteria to select patients for both phase 2 and 3 trials. Additionally, interest is growing in the design of preventive clinical trials in ARDS and to initiate early treatment of patients with acute lung injury before the need for endotracheal intubation. We also present promising new approaches to treating ARDS, including combination therapies, cell-based therapies, and generic pharmacological compounds with low-risk profiles that are already in routine clinical use for other clinical indications.

To review: a) the role of extravascular fibrin deposition in the pathogenesis of acute lung injury; b) the abnormalities in the coagulation and fibrinolysis pathways that promote fibrin deposition in the acutely injured lung; and c) the pathways that contribute to the regulation of the fibrinolytic system via the lung epithelium, including newly recognized posttranscriptional and urokinase-dependent pathways. Another objective was to determine how novel anticoagulant or fibrinolytic strategies may be used to protect against acute inflammation or accelerated fibrosis in acute lung injury. Published medical literature. Alveolar fibrin deposition is characteristic of diverse forms of acute lung injury. Intravascular thrombosis or disseminated intravascular coagulation can also occur in the acutely injured lung. Extravascular fibrin deposition promotes lung dysfunction and the acute inflammatory response. In addition, transitional fibrin in the alveolar compartment undergoes remodeling leading to accelerated pulmonary fibrosis similar to the events associated with wound healing, or desmoplasia associated with solid neoplasms. In acute lung injury, alveolar fibrin deposition is potentiated by consistent changes in endogenous coagulation and fibrinolytic pathways. Procoagulant activity is increased in conjunction with depression of fibrinolytic activity in the alveolar compartment. Initiation of the procoagulant response occurs as a result of local overexpression of tissue factor associated with factor VII. Depression of fibrinolytic activity occurs as a result of inhibition of urokinase plasminogen activator (uPA) by plasminogen activators, or series inhibition of plasmin by antiplasmins. Locally increased amplification of plasminogen activator inhibitor-1 (PAI-1) is largely responsible for this fibrinolytic defect. Newly described pathways by which lung epithelial cells regulate expression of uPA, its receptor uPAR, and PAI-1 at the posttranscriptional level have been identified. These pathways operate by cis-trans interactions between mRNA binding proteins; regulatory sequences within these mRNAs control their stability. The regulatory mechanisms seem to involve multiple protein-mRNA interactions, and the phosphorylation state of the proteins appears to determine whether complex formation of, or dissociation from, the regulatory sequences occurs. uPA is capable of inducing its own expression in lung epithelial cells as well as that of uPAR and PAI-1-the effects involve posttranscriptional regulatory components. These and related observations have led to the implementation of anticoagulant or fibrinolytic strategies to protect the lung against acute lung injury. The success of new fibrinolytic strategies to block pleural loculation suggests that a similar approach might be used to prevent accelerated pulmonary fibrosis, which can occur in association with many forms of acute lung injury. Disordered coagulation and fibrinolysis promote extravascular fibrin deposition in acute lung injury. It is this deposition that characterizes acute lung injury and repair. Expression of uPA, uPAR, and PAI-1 by the lung epithelium, as well as the ability of uPA to induce other components of the fibrinolytic system, involves posttranscriptional regulation. These pathways may contribute to disordered fibrin turnover in the injured lung. The success of anticoagulant or fibrinolytic strategies designed to reverse the abnormalities of local fibrin turnover in acute lung injury supports the inference that abnormalities of coagulation, fibrinolysis, and fibrin deposition have a critical role in the pathogenesis of acute lung injury.

Poor research reporting is a major contributing factor to low study reproducibility, financial and animal waste. The ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines were developed to improve reporting quality and many journals support these guidelines. The influence of this support is unknown. We hypothesized that papers published in journals supporting the ARRIVE guidelines would show improved reporting compared with those in non-supporting journals. In a retrospective, observational cohort study, papers from 5 ARRIVE supporting (SUPP) and 2 non-supporting (nonSUPP) journals, published before (2009) and 5 years after (2015) the ARRIVE guidelines, were selected. Adherence to the ARRIVE checklist of 20 items was independently evaluated by two reviewers and items assessed as fully, partially or not reported. Mean percentages of items reported were compared between journal types and years with an unequal variance t-test. Individual items and sub-items were compared with a chi-square test. From an initial cohort of 956, 236 papers were included: 120 from 2009 (SUPP; n = 52, nonSUPP; n = 68), 116 from 2015 (SUPP; n = 61, nonSUPP; n = 55). The percentage of fully reported items was similar between journal types in 2009 (SUPP: 55.3 ± 11.5% [SD]; nonSUPP: 51.8 ± 9.0%; p = 0.07, 95% CI of mean difference -0.3–7.3%) and 2015 (SUPP: 60.5 ± 11.2%; nonSUPP; 60.2 ± 10.0%; p = 0.89, 95%CI -3.6–4.2%). The small increase in fully reported items between years was similar for both journal types (p = 0.09, 95% CI -0.5–4.3%). No paper fully reported 100% of items on the ARRIVE checklist and measures associated with bias were poorly reported. These results suggest that journal support for the ARRIVE guidelines has not resulted in a meaningful improvement in reporting quality, contributing to ongoing waste in animal research.