Endogenous fibrinolytics
Fibrin deposition and clearance is regulated by the control of plasmin activity, which in turn is regulated by the relative balance between plasminogen activators and plasminogen activator inhibitors (PAI)-1, -2 and -3. Plasminogen is mainly synthesised in the liver and converted into plasmin by the serine proteinases tissue-type plasminogen activator (tPA) or urokinase-type plasminogen activator (uPA). Several preclinical and clinical studies have demonstrated elevated levels of PAI-1 in pneumonia [30, 71, 72]. However, preclinical studies on the effects of PAI-1, tPA and uPA in murine models of pneumonia suggest the outcome is pathogen dependent. For example, in a Klebsiella pneumoniae pneumonia model, PAI-1 improved bacterial clearance and reduced mortality [73], but neither PAI-1 nor plasmin appeared to have a role in mouse models of S. pneumoniae [72] or Pseudomonas aeruginosa pneumonia [74]. Instead, the urokinase plasminogen activator receptor axis promoted host defence against S. pneumoniae by recruiting neutrophils to the alveoli and enhancing neutrophil-mediated bacterial killing [75]. Furthermore, in a model of sterile lung injury, tPA administration reduced alveolar leak but had no effect on pulmonary inflammation [76]. Data are limited regarding the role of this system in viral respiratory infection models but in a study of influenza A infection, the absence of plasminogen reduced inflammation [77]. A recent meta-analysis of preclinical studies of fibrinolytics in acute lung injury suggested increased fibrinolysis, attenuated inflammation and alveolar leak, and improved survival [78].
There are limited clinical data on the efficacy of targeting fibrinolysis in patients with severe infections or ARDS. However, patients with ARDS display evidence of a marked reduction in fibrinolysis, with evidence of reduced uPA activity and increased PAI-1 levels in bronchoalveolar lavage fluid [30]. Furthermore, one study demonstrated a shorter length of stay in the intensive care unit and improved survival in ARDS patients treated with nebulised streptokinase [79]; this pathway may represent an interesting target for the management of COVID-19-induced lung injury. Two trials targeting this pathway are currently underway, one in the UK (nebulised r-tPA) and another in the USA (alteplase) (NCT04356833, NCT04357730).