Role of coagulation cascade proteases in lung repair and fibrosis.

Abstract

The specific aims of this presentation are: 1) to review the evidence that activation of the coagulation cascade is a common feature of fibrotic lung disease and other respiratory conditions associated with excessive deposition of extracellular matrix; 2) to describe the profibrotic effects of coagulation proteases and the signalling receptors involved; and 3) to provide evidence that coagulation proteases and their signalling receptors contribute to experimentally induced lung fibrosis. The fragile architecture of the lung is constantly under threat from both external and internal insults. When these insults lead to damage of the extensive vascular network of the lung, activation of the coagulation cascade (fig. 1⇓) ensures that there is minimal blood loss by temporarily plugging damaged vessels with a stable clot consisting of aggregated platelets enmeshed in fibrin. However, excessive or smouldering activation of the coagulation cascade has been implicated in promoting lung inflammation and subsequent interstitial and alveolar fibrosis 1, 2. Intra-alveolar accumulation of fibrin occurs in the lungs of patients with pulmonary fibrosis 3, in acute lung injury and in the acute respiratory distress syndrome (ARDS) 4, in which rapid fibroproliferation and matrix synthesis can lead to the development of extensive fibrotic lesions. Bronchoalveolar lavage fluid from patients with ARDS has also been reported to contain tissue factor-factor VII/VIIa complexes that can trigger activation of the extrinsic coagulation cascade 4. Levels of active thrombin have been shown to be increased in the lungs of patients with pulmonary fibrosis associated with …