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.

Figure 1

Alveolar architecture of normal and fibrotic lung. Images show the stark contrast in alveolar architecture in the normal and fibrotic lung. In the fibrotic lung, the open alveolar architecture is obliterated and replaced with dense fibrotic tissue. (Histology slides courtesy of Dr Robin McAnulty, Centre for Respiratory Research, University College London.)

Figure 2

Activation of proteinase-activated receptors (PARs). Activation of PARs involves proteolytic cleavage of the N terminus leading to the unmasking of a tethered ligand, which subsequently binds to the second extracellular loop of the seven transmembrane domain receptor. This leads to a conformational change at the C terminus and recruitment of heterotrimeric G proteins.

Figure 3

Proteinase-activated receptors (PARs) perpetuate the interplay between coagulation and inflammation. Activation of PARs leads to the induction of potent pro-inflammatory mediators, which are capable of inducing tissue factor expression. Tissue factor initiates the activation of the extrinsic coagulation pathway resulting in activation of PARs. The functional consequences in the injured lung include microvascular permeability, fibrin deposition, leukocyte recruitment and fibroblast activation.

Figure 4

Role of proteinase-activated receptor 1 (PAR₁) in orchestrating the response to lung injury. The left-hand side shows the normal alveolar structure with flattened alveolar type I cells (AECI), sparse cuboid type II cells (AECII) and interstitial fibroblasts. Also shown is the microvasculature lined by endothelial cells. The right-hand side shows the effect of lung injury to the lung leading to denudation of the alveolar epithelium, hyperproliferation of AECIIs, inflammatory cell recruitment, microvascular permeability and proliferation and differentiation of fibroblasts. Activation of PAR1 on multiple cell types plays a central role in influencing a number of these processes (1–6). The in vivo role of all of these pathways remains to be established, but current experimental evidence supports a major role for PAR1 in promoting microvascular leak, inflammatory cell recruitment and fibroproliferative responses. Abbreviations: AECI, AECII, type I and II alveolar epithelial cells; EC, endothelial cell.