Review ArticleThe plasmin system in 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
References (87)
- et al.
Purification and characterization of a plasminogen activator inhibitor from the histiocytic lymphoma cell line U-937
J. Biol. Chem.
(1986) - et al.
The role of up-regulated serine proteases and matrix metalloproteinases in the pathogenesis of a murine model of colitis
Am. J. Pathol.
(2000) - et al.
Matrix metalloproteinase-12 is expressed in phagocytotic macrophages in active multiple sclerosis lesions
J. Neuroimmunol.
(2003) - et al.
Extracellular matrix remodeling in the vascular wall
Pathol. Biol. (Paris)
(2001) - et al.
Protease antigens from house dust mite
Lancet
(1989) - et al.
Triggering of the vascular permeability reaction by activation of the Hageman factor–prekallikrein system by house dust mite proteinase
Biochim. Biophys. Acta
(1991) - et al.
Activation of human serum complement with allergens: I. Generation of C3a, C4a, and C5a and induction of human neutrophil aggregation
J. Allergy Clin. Immunol.
(1987) - et al.
Macrophage fibrinolytic activity: identification of two pathways of plasmin formation by intact cells and of a plasminogen activator inhibitor
Cell
(1982) - et al.
Regulation of plasminogen activation by interleukin-6 in human lung fibroblasts
Biochim. Biophys. Acta
(1994) - et al.
Interleukin-4 suppresses plasminogen activator inhibitor-2 formation in stimulated human monocytes
Blood
(1992)
Macrophage colony-stimulating factor and granulocyte-macrophage colony-stimulating factor stimulate the synthesis of plasminogen-activator inhibitors by human monocytes
Blood
Human mast cell tryptase activates single-chain urinary-type plasminogen activator (pro-urokinase)
J. Biol. Chem.
Contact activation triggers stimulation of the monocyte 5-lipoxygenase pathway via plasmin
Blood
Plasmin-induced expression of cytokines and tissue factor in human monocytes involves AP-1 and IKKbeta-mediated NF-kappaB activation
Blood
Airways remodeling is a distinctive feature of asthma and is related to severity of disease
Chest
PAI-1 promotes extracellular matrix deposition in the airways of a murine asthma model
Biochem. Biophys. Res. Commun.
Major genes regulating total serum immunoglobulin E levels in families with asthma
Am. J. Hum. Genet.
The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells
J. Biol. Chem.
Possible role of the 4G/5G polymorphism of the plasminogen activator inhibitor 1 gene in the development of asthma
J. Allergy. Clin. Immunol.
C5a stimulates production of plasminogen activator inhibitor-1 in human mast cells and basophils
Blood
The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system
Am. J. Pathol.
Plasminogen activator inhibitor type 2: a regulator of monocyte proliferation and differentiation
Blood
Protection from tumor necrosis factor-mediated cytolysis by overexpression of plasminogen activator inhibitor type-2
J. Biol. Chem.
Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor alpha-induced apoptosis. Evidence for an alternate biological function
J. Biol. Chem.
Urokinase induces expression of its own receptor in Beas2B lung epithelial cells
J. Biol. Chem.
The plasminogen activator/plasmin system
J. Clin. Invest.
Plasminogen activator inhibitors–a review
Enzyme
Assessment of the relative contribution of different protease inhibitors to the inhibition of plasmin in vivo
Thromb. Haemost.
Synovial tissue protease gene expression and joint erosions in early rheumatoid arthritis
Arthritis Rheum.
The induction of pulmonary emphysema with human leukocyte elastase
Am. Rev. Respir. Dis.
Plasmin regulates the activation of cell-associated latent TGF-beta 1 secreted by rat alveolar macrophages after in vivo bleomycin injury
Am. J. Respir. Cell. Mol. Biol.
Thrombin signalling and protease-activated receptors
Nature
Affinity purification of a major Alternaria allergen using a monoclonal antibody
Ann. Allergy
Receptor-mediated antigen delivery into macrophages. Complexing antigen to alpha 2-macroglobulin enhances presentation to T cells
J. Immunol.
Effects of treatment on airway inflammation and thickening of basement membrane reticular collagen in asthma. A quantitative light and electron microscopic study
Am. Rev. Respir. Dis.
Proliferation of asthmatic and non asthmatic smooth muscle cells in culture-effect of formoterol and budesonide
Am. J. Respir. Crit. Care Med.
The mast cell as site of tissue-type plasminogen activator expression and fibrinolysis
J. Immunol.
Regulation of the synthesis and secretion of plasminogen activators by endothelial cells
Haemostasis
Distribution of plasminogen activator inhibitor (PAI-1) in tissues
J. Clin. Pathol.
Inflammation and structural changes in the airways of patients with atopic and nonatopic asthma. BHR Group
Am. J. Respir. Crit. Care Med.
Plasmin-induced proteolysis of tenascin-C: modulation by T lymphocyte-derived urokinase-type plasminogen activator and effect on T lymphocyte adhesion, activation, and cell clustering
J. Immunol.
Integrin-dependent induction of functional urokinase receptors in primary T lymphocytes
J. Clin. Invest.
Production of plasminogen activator inhibitor-1 by human mast cells and its possible role in asthma
J. Immunol.
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2012, Experimental and Molecular PathologyCitation Excerpt :Airway remodeling is characterized by structural changes within the airway wall, including smooth muscle hypertrophy, basement membrane thickening, submucosal fibrosis, mucus cell metaplasia, epithelial shedding, and angiogenesis (Gizycki et al., 1997). Among the various factors involved in the pathogenesis of remodeling, we focused on serine peptidase inhibitor clade E member 1 (SERPINE1, also known as plasminogen activator inhibitor-1, PAI-1) and the process of epithelial–mesenchymal transition (EMT) in epithelial cells (Hackett et al., 2009; Kowal et al., 2008; Kucharewicz et al., 2003; Kuramoto et al., 2009; Miyamoto et al., 2011). SERPINE1 regulates extracellular matrix (ECM) proteolysis (Kowal et al., 2008; Kucharewicz et al., 2003), and the attenuation of SERPINE1 has been reported to exhibit therapeutic properties for airway remodeling (Kuramoto et al., 2009; Miyamoto et al., 2011).