Procoagulant signalling mechanisms in lung inflammation and fibrosis: novel opportunities for pharmacological intervention?

• Published in: British journal of pharmacology 2008-03, Vol.153 (S1), p.S367-S378
• Main Author: Chambers, R C
• Format: Article
• Language: English
• Subjects: acute lung injury; Animals; Anticoagulants - therapeutic use; Blood Coagulation - physiology; coagulation cascade; Fibrinolysis; fibroblast; Humans; Mice; Mice, Knockout; Pneumonia - blood; Pneumonia - drug therapy; Pneumonia - pathology; proteinase‐activated receptor; pulmonary fibrosis; Pulmonary Fibrosis - blood; Pulmonary Fibrosis - drug therapy; Pulmonary Fibrosis - pathology; Receptor, PAR-1 - agonists; Receptor, PAR-1 - antagonists & inhibitors; Receptor, PAR-1 - physiology; Respiratory Distress Syndrome, Adult - drug therapy; Respiratory Distress Syndrome, Adult - pathology; Respiratory Distress Syndrome, Adult - physiopathology; Review; Signal Transduction - drug effects; thrombin
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0707603

There is compelling evidence that uncontrolled activation of the coagulation cascade following lung injury contributes to the development of lung inflammation and fibrosis in acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and fibrotic lung disease. This article reviews our current understanding of the mechanisms leading to the activation of the coagulation cascade in response to lung injury and the evidence that excessive procoagulant activity is of pathophysiological significance in these disease settings. Current evidence suggests that the tissue factor‐dependent extrinsic pathway is the predominant mechanism by which the coagulation cascade is locally activated in the lungs of patients with ALI/ARDS and pulmonary fibrosis. Whilst, fibrin deposition might contribute to the pathophysiology of ALI/ARDS following systemic insult; current evidence suggests that the cellular effects mediated via activation of proteinase‐activated receptors (PARs) may be of particular importance in influencing inflammatory and fibroproliferative responses in experimental models involving direct injury to the lung. In this regard, studies in PAR1 knockout mice have shown that this receptor plays a major role in orchestrating the interplay between coagulation, inflammation and lung fibrosis. This review will focus on our current understanding of excessive procoagulant signalling in acute and chronic lung injury and will highlight the novel opportunities that this may present for therapeutic intervention. British Journal of Pharmacology (2008) 153, S367–S378; doi:10.1038/sj.bjp.0707603; published online 28 January 2008