© 2005 American Thoracic Society DOI: 10.1165/rcmb.F304
No Bit PARt for PAR-1The Rayne Institute, University College London Medical School, London, United Kingdom Correspondence and requests for reprints should be addressed to Geoffrey J. Laurent, Ph.D., The Rayne Institute, University College London Medical School, 5 University Street, London WC1E 6JJ, UK. E-mail: gjloffice{at}ucl.ac.uk This issue of the Journal (pp. 231–247) contains an article that expands our understanding of the role of proteolytically activated receptors (PARs) in respiratory cell and molecular biology (1). It reports that neutrophil elastase is a potential activator of PARs and proposes this activation leads to apoptosis of epithelial cells. This novel activation pathway is of interest given the well-established role of neutrophil elastase in respiratory diseases, particularly chronic obstructive pulmonary disease (COPD) (2), but more recently pulmonary fibrosis (3, 4). More on this later, but first some background on PARs and coagulation. The coagulation cascade has long been the stuff of cardiology. This belief has, if anything, expanded in recent years with current thinking that plaque rupture and consequent thrombus formation, rather than progressive lipid deposition, is key in the setting of most acute and chronic cardiovascular diseases. In respiratory medicine, coagulation cascade activity, with fibrin deposition, had long been described in both acute and chronic lung diseases, but its role in pathogenesis remains less certain. Coagulation Cascade in Respiratory Diseases Coagulation cascade activity, with generation of a large family of serine proteases, and subsequent clot formation is recognized as an important early event in acute respiratory diseases such as acute respiratory distress syndrome (ARDS) (reviewed in Ref. 5). The presence of the so-called hyaline membranes (fibrin deposits) is a central feature of pathology and provides the provisional scaffold into which mesenchymal cells migrate, leading to the remodeling which in ARDS can rapidly destroy the lungs' fine structure due to gross scarring with extensive collagen deposition. These changes in coagulation cascade homeostasis are also seen in more chronic diseases, including asthma (6, 7), COPD (8, 9), pulmonary hypertension (10), and pulmonary fibrosis (11–14). Similar correlations are reported in lung cancer (15), but again their significance in pathogenesis is uncertain. Of interest, however, is a recent report suggesting a role for PAR-1 activation by matrix metalloprotease (MMP) 1 as a key event in breast tumor invasion (16). This matches nicely with the pioneering concepts proposed by Dvorak, who, almost twenty years ago, described tumors as "wounds that do not heal" (17). In all these diseases the products of this cascade, including the serine proteases, have been proposed to play a role in the injury response and subsequent tissue remodeling. Thus an alternative view for the evolution of respiratory diseases has arisen based around the hypothesis that enzymes and products of coagulation play a key role (Figure 1).
Mechanisms ... More Mechanisms How do coagulation cascade proteinases and products play a role in these respiratory diseases? First, fibrin acts as a scaffold for platelets and inflammatory cells. Thus any changes favoring fibrin deposition or preventing its removal could favor chronicity (18). This concept is supported by the observation that mice overexpressing plasminogen activator inhibitor-1 gene are more susceptible to pulmonary fibrosis, and that mice in which this gene is deleted are protected (19). Second, the various serine proteases, acting via interactions with specific receptors, are potent activators of inflammatory cascade and activation of fibroblasts and smooth muscle cells. Thus, tissue factor, thrombin, factor VII (likely with other proteases), and factor Xa can all influence a host of cellular responses acting via a family of at least four PARs (Figure 2).
PAR-1 and the Pathogenesis of Respiratory Diseases PAR-1 is emerging as a central receptor in the setting of several respiratory diseases and is currently an important target for pharmaceutical development (reviewed in Refs. 20 and 21). PAR-1 is expressed on inflammatory cells (including macrophages) and many resident cells of the lung. Its activation leads to altered airway and arterial tone, to enhanced cell proliferation, to increased cytokine production, to production of many matrix proteins, to enhanced apoptosis, cytoskeletal remodeling, and cell migration (reviewed in Ref. 21). Of course, this does not prove it plays central or causal roles in pathogesis. More instructive on this issue has been the generation of PAR-1 knockout mice by Sean Coughlin, who first cloned and described PAR-1 (reviewed in Ref. 22). These mice have recently been shown to be partially protected from bleomycin-induced acute lung injury and fibrosis (23). Furthermore, this article suggests that this protection may be due to attenuated production of MCP1, TGF-ß, and CTGF, mediators implicated in the pathogenesis of fibrosis and known to be produced in response to PAR-1 agonists (24). Activation of PAR-1 by Neutrophil Elastase The potential role of PAR-1 has widened considerably with the discovery that it can be activated by a large number of proteases (Figure 2). One of these reported activators is leukocyte elastase, which is the subject of the article by Downey and colleagues in this issue of the Journal (1). This article suggests that elastase leads to the activation of PAR-1 on epithelial cells leading to apoptosis. Such actions, if they occur in vivo, are of great interest given that apoptosis is hypothesized to be central to the course of both acute and chronic lung diseases (25, 26). The challenge as always is to establish the importance of this pathway in vivo, but the concepts certainly make us rethink the breadth of involvement of PARs, and in particular PAR-1, in acute and chronic lung diseases. Many challenges remain. For example, we must await more studies that better define the precise mechanistic link between neutrophil elastase and PAR-1 in epithelial cell apoptosis. Wider assessment of this phenomenon is also required given reports in the literature that argue against neutrophil elastase being a PAR-1 agonist (27–29). It should be noted, however, that these studies were in nonepithelial cells, raising the possibility of cell specificity via mechanisms as yet not fully defined. Many other more general questions remain unanswered. In human respiratory diseases, or animal models in which a PAR-1 role is demonstrated, it is unclear which are the key cells in PAR-1 responses and in what, if any, aspect of the disease process they participate. Implications of this Area of Research for Treatment of Respiratory Diseases In respiratory medicine, our concepts of pathogenesis of both acute and chronic diseases has focused on inflammatory cells and their products as the central players. Most credence to this approach comes from our experience in asthma, where the presence of activated inflammatory cells is key. Further, in this disease setting, corticosteroids, our most effective anti-inflammatory drug, successfully control the symptoms of most patients. Similar hypotheses were constructed for other chronic respiratory diseases such as COPD, ARDS, and pulmonary fibrosis. However, challenges to this hypothesis have arisen based largely on the ineffective results with corticosteroids in the setting of these diseases. It is this failure which has lead to the hypothesis that damaged and activated resident cells, such as epithelial cells, may play central roles (30). With the caveat that the current work by Downey and colleagues is conducted entirely on isolated cells, its message that PAR-1 might be central to epithelial cell apoptosis provides an important additional piece of data that further encourages us to learn more about these receptors and explore agents that by blocking its function may have roles in the setting of respiratory diseases. Furthermore, if neutrophil elastase is confirmed as a key activator of PAR-1, this means that PAR-1 is an interesting target for chronic obstructive lung diseases. We eagerly await more data from our animal models of COPD and other diseases and eventually trials in humans with compounds now under development. Acknowledgments Almost all of this editorial is built on knowledge acquired from great colleagues and collaborators over many years. There are too many to mention them all, but the author would particularly like to thank Rachel Chambers, Karim Dabbagh, Olivier Blanc-Brude, Gisli Jenkins, Andy Peacock, Steve Idell, and the late Jack Reeves. He should also recognize the Jeremy Bentham pub, London W1, that so often fueled these discussions. Footnotes Conflict of Interest Statement: G.J.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this paper. Received in final form June 22, 2005
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