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

Abstract

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 PAR 1 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.

Protease-Activated Receptor-2 Induces Myofibroblast Differentiation and Tissue Factor Up-Regulation during Bleomycin-Induced Lung Injury

“…9 Over recent years, this observation led to the hypothesis that uncontrolled activation of the coagulation cascade following lung injury would contribute to the development of lung inflammation and fibrosis in acute lung injury/acute respiratory distress syndrome and fibrotic lung disease. 32,33 In the present study, we provide several lines of evidence strongly suggesting that PAR-2 is indeed important in the pathogenesis of lung fibrosis. We show that the coagulation cascade is indeed activated in the BALF of patients with idiopathic pulmonary fibrosis, the most devastating pulmonary fibrotic disease.…”

Inhibition of Coagulation Activation and Inflammation by a Novel Factor Xa Inhibitor Synthesized from the Earthworm Eisenia andrei

“…PAR activation induces a wide variety of inflammatory conditions, such as sepsis, myocardial infarction, stroke, acute lung injury and glomerulonephritis. 25,26) In order to address potential roles of ESP in the PAR pathway, we examined whether ESP effectively inactivated FXa and thereby inhibited signaling pathways. The results from this experiment showed that ESP well inhibited ERK1/2 phosphorylation, followed by a dramatic reduction of NO production as compared to the ASP group.…”

Inhibition of Thrombin as a Novel Strategy in the Treatment of Scleroderma-Associated Interstitial Lung Disease

“…The relative protection from pulmonary fibrosis observed in this model is a reduction in expression of two major fibrogenic growth factors, CTGF and transforming growth factor -(TGF-), as well as a reduction of the chemokine (C-C motif) ligand 2 (CCL2)/monocyte chemotactic protein 1 (MCP-1). Elevated expression of PAR-1 has been shown in patients with IPF and in a murine model of bleomycin-induced lung fibrosis (Chambers, 2008;Howell et al, 2005). In previous studies we demonstrated that PAR-1 expression is also dramatically increased in lung tissue from scleroderma patients, mainly in lung parenchyma in context with myofibroblasts present in inflammatory and fibroproliferative foci (Bogatkevich et al, 2005).…”

“…In addition to its essential role in coagulation, thrombin has several important functions at a cellular level, both in normal health and in multiple disease processes, including pulmonary fibrosis (Chambers, 2008). Our laboratory as well as others has demonstrated dramatically increased levels of thrombin in BALF from scleroderma patients with lung fibrosis and other fibrosing lung diseases (Ohba et al, 1994;Hernadez-Rodriguez et al, 1995).…”