Background: ARDS is characterized by inflammation of the lung parenchyma and alterations of the alveolar haemostasis with extravascular fibrin deposition. Factor VII-activating protease (FSAP) is a recently described serine protease in plasma and tissues, known to be involved in haemostasis, cell proliferation and migration.
Methods: We investigated FSAP protein (western blotting/ELISA/immunohistochemistry) and activity (coagulation/fibrinolysis assays) in plasma, bronchoalveolar lavage (BAL) fluids and lung tissue of mechanically ventilated patients with early ARDS as compared to patients with cardiogenic pulmonary oedema and healthy controls. Cell culture experiments were performed to assess the influence of different inflammatory stimuli on FSAP expression by various cell populations of the lung.
Results: FSAP protein level and activity were markedly increased in ARDS plasma and BAL fluids, thus significantly contributing to the increased alveolar procoagulant activity. In ARDS lungs, immunoreactivity for FSAP was observed in alveolar macrophages, bronchial epithelial and endothelial cells, as compared to controls, in which immunoreactivity for FSAP was restricted to alveolar macrophages. Only a low basal FSAP expression was detected in these cell populations. However, LPS and IL-8 induced FSAP-specific mRNA expression in human lung microvascular endothelial and in bronchial epithelial cells. We further demonstrated that FSAP is taken up by alveolar macrophages and degraded within the lysosomal compartment.
Conclusions: Increased levels and an altered cellular expression pattern of FSAP are found in ARDS lungs. This may represent a novel pathological mechanism contributing to pulmonary extravascular fibrin deposition. In addition, this may modulate inflammation in the acutely-injured lung via haemostasis-independent cellular activities of FSAP.
- acute lung injury
- acute respiratory distress syndrome
- factor VII and single-chain plasminogen activator-activating protease
- hyaluronan binding protein 2