Review Article
The plasmin system in airway remodeling

https://doi.org/10.1016/j.thromres.2003.10.011Get rights and content

Abstract

Recent studies suggest that the plasmin system plays an active role in tissue remodeling. Plasmin degrades the extracellular matrix (ECM), either directly removing glycoproteins from ECM or by activating matrix metalloproteinases (MMPs). PAI-1 blocking MMPs may prevent ECM degradation, but inhibiting fibrinolysis leads to fibrin accumulation and fibrosis. Components of the plasmin system including tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), and plasminogen activator inhibitors PAI-1 and PAI-2 are synthesised by airway cells, and inflammatory mediators affect their expression. The plasmin system, in turn, actively influences the production of inflammatory mediators and growth factors, extending pathological structural changes in the airway. Modulation of the plasmin system might be a new pharmacological strategy that could inhibit the development of airway remodeling.

Introduction

The plasmin system consists of serine proteases and their inhibitors. Activation of this system depends on an enzymatic chain reaction that proceeds from the conversion of proenzyme plasminogen into the active serine protease—plasmin. This step is controlled by two trypsin-like proteases, namely tissue plasminogen activator (t-PA) and urokinase plasminogen activator (u-PA) [1]. In vivo, plasminogen activator inhibitors (PAI-1, PAI-2) play a crucial role in the regulation of serine protease activity [2]. Even though, PAI-2 exhibits inhibitory activity toward t-PA and u-PA, its efficiency is 20- to-100-fold less than that of PAI-1 [3]. The local activity of plasmin remains also under the control of α2-antiplasmin and α2-macroglobulin [4] (Fig. 1).

Recently, the crucial role of proteases and their inhibitors in the process of tissue repair has been demonstrated. Activation of a broad spectrum of proteolytic enzymes is associated with the process of wound healing as well as with the acute and chronic phases of inflammatory response. Involvement of proteolytic enzymes in the remodeling of different tissues has been demonstrated in rheumatoid arthritis, pulmonary emphysema, colitis, multiple sclerosis and atherosclerosis [5], [6], [7], [8], [9]. The mechanism of protease action is not restricted to extracellular matrix protein degradation, but also their involvement in the regulation of mediators and growth factors activity as well as direct modulation of cell function via membrane receptors has been demonstrated [10], [11]. Exogenous proteases may also play an important role in the pathogenesis of respiratory diseases including bronchial asthma. In fact, many of the individual proteins of commonly encountered allergens possess proteolytic activity [12], [13]. The broadest spectrum of proteases is encountered in house dust mite and mold allergens. Major house dust mite allergens possess proteolytic activity: Der p I is a cysteine protease, while Der p III is a serine protease. The ability of Der p I to directly activate both complement and kinin systems is dependent on its proteolytic activity [14], [15]. It could be speculated therefore that an efficiently working antiprotease system may play an important role in the regulation of defence mechanisms against allergens. Protease inhibitors are crucial for controlling protease activity, but they also play an important role in innate immunity, including antigen recognition and antigen clearance by mononuclear phagocytes [16].

Airway remodeling is a distinctive feature of asthma and it is related to the severity of the disease. Interestingly, application of currently available medications, mainly corticosteroids, has been very successful in inhibiting airway inflammation, but they exert a very mild effect on reducing the structural changes in the airways [17], [18]. Therefore, the understanding pathophysiology of the remodeling process may help in creating new treatment strategies, which may protect against the development of irreversible changes in the airways.

Section snippets

The plasmin system regulation

An increasing body of evidence indicates that many of the components of the plasmin system including, t-PA, u-PA, PAI-1 and PAI-2, are synthesised by airway cells. The main cells responsible for production of plasminogen activators are endothelial cells, fibroblasts, epithelial cells, mast cells, monocytes/macrophages and smooth muscle cells [19], [20], [21], while plasmin system inhibitors are synthesised by endothelium, platelets and megakaryocytes, neutrophils, monocytes/macrophages, smooth

The plasmin system in inflammatory processes

The plasmin system also influences cellular functions without involving proteolytic activity. It has been shown that plasmin may enhance inflammation by inducing neutrophil aggregation, platelet degranulation, and the release of arachidonic acid derivatives [39], [40], [41]. In addition, it activates human peripheral blood monocytes to release lipid mediators, such as cysteinyl leukotrienes and leukotriene B4, but does not influence the release of prostaglandin E2 or tromboxan A2 [42]. Syrovets

The plasmin system in airway remodeling

Morphologically, in the airways of bronchial asthma patients, several structural changes can be observed [48], [49]. In bronchial biopsies from asthmatics—besides epithelial cell damage and infiltration of the bronchial wall by inflammatory cells such as T cells, eosinophils, and monocytes—irreversible abnormalities can also be found [23]. These irreversible changes include increased deposition of extracellular matrix proteins in the bronchial wall, hyperplasia and hypertrophy of smooth muscle

Summary

The plasmin system is activated in the airways of asthmatics. Both inflammatory cells and airway resident cells are a potent source of plasmin activators and inhibitors. Moreover, allergic reaction mediators can increase the expression of plasmin system components. Functional studies indicate that inadequate regulation of plasmin system activation may lead to irreversible structural changes in the airways. A balance between the activation of inflammatory cells, released mediators, and plasmin

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