A summary of findings from studies that have targeted ECM proteases and receptors in experimental models of lung and vascular disease. The animal models used were: (i) Acute pulmonary thromboembolism (APT), Which is induced with autologous blood clots; (ii) Allergen, A model of allergic airway inflammation which has characteristics of asthma pathology. In the model, antigen sensitized animals are repeatedly challenged with aerosolized antigen (e.g., ovalbumin, house dust mite extract); (iii) Balloon angioplasty, A vascular intervention procedure which causes restenosis; (iv) Bleomycin, Intranasal administration of bleomycin induces acute lung injury and subsequent pulmonary inflammation and fibrosis. This model also features extensive remodeling in the upper airways involving ASM cell hypertrophy and hyperplasia; (v) Endotoxin, Intranasal administration of endotoxin (i.e., lipopolysaccharide or LPS) also induces acute lung injury and pulmonary inflammation; and (vi) Hypoxia, A model of pulmonary arterial hypertension (PAH).
Alterations in smooth muscle cell function and phenotype contribute to tissue remodeling in various pathologies including obstructive lung (e.g., asthma) and vascular (e.g., atherosclerosis) diseases. The extracellular matrix (ECM) is a major influence on the biology of smooth muscle cells, being an important support structure that provides signaling cues through its biochemical and biophysical properties. ECM factors activate biochemical and mechano-transduction signaling pathways, which modulate smooth muscle cell contraction, stiffness, survival, growth, cytokine production and migration (i.e., cellular processes which contribute to changes in tissue architecture). The interaction of the ECM with smooth muscle cells is a dynamic multi-directional process, as smooth muscle cells also produce ECM protein, as well as proteases and cross-linking enzymes which regulate ECM form and structure. Understanding the molecular basis of ECM modifications and their impact on smooth muscle cell function in disease may lead to the development of novel therapies. This chapter reviews interactions between the ECM and smooth muscle cell and how they become altered in disease, using obstructive lung and vascular diseases as examples. From a pharmacological and therapeutic perspective, strategies that alter the phenotype of the smooth muscle cell in disease will be discussed. Emphasis will be given to approaches that target the proteases and mediators of ECM-smooth muscle cell signaling as potential treatments for pulmonary and vascular disease. Proteases of the coagulation and plasminogen activation systems have been given particular attention as they not only have a role in forming and modifying ECM, but also can directly stimulate changes in smooth muscle cell function and phenotype via activating receptors such as the protease-activated receptor-1 (PAR-1) and integrins.
- Extracellular matrix (ECM)
Smooth muscle cells function by contracting following activation of actin and myosin filaments, in a process involving myosin light chain phosphorylation, mediated by Ca2+-dependent pathways . In many diseases, alterations in smooth muscle cell function including contractile responses, growth and phenotype, contribute to tissue remodeling. In obstructive lung diseases such as severe asthma and chronic obstructive pulmonary disease (COPD), increases in the stiffness and mass of the airway smooth muscle (ASM) bundle contribute to fixed airway obstruction and hyper-responsiveness [2, 3]. In vascular injury and diseases such as atherosclerosis and pulmonary arterial hypertension (PAH), the migration, stiffening, proliferation and growth of vascular smooth muscle (VSM) cells contribute to the enlargement of the blood vessel wall, which in effect reduces lumen size, thus an increase in vascular resistance [4, 5]. Alterations in the microenvironment of the smooth muscle cell, particularly in the composition and structure of the ECM, accompany changes in smooth muscle biology in disease. Smooth muscle cells have a large role in modifying their microenvironment in disease by producing ECM protein (
2. Smooth muscle cells
Smooth muscle cells are phenotypically-plastic stromal cells, which are very capable of differentiating in response to injury and inflammation in disease. Whilst myogenic, the structure, mechanical properties, contractility and function of smooth muscle cells are different to those of striated and cardiac muscle cells. The involuntary non-striated smooth muscle cells are found in many tissues and organs including the gastro-intestinal tract, the respiratory system, reproductive tract, urinary bladder, skin, iris of the eyes, kidneys and blood vessels. Smooth muscle cells contract and relax to regulate the luminal diameter and viscoelasticity of conducting vessels (
3. Smooth muscle cells in disease
Structural and functional changes to smooth muscle cells and their microenvironment contributes to tissue remodeling in diseases such as lung obstructive and vascular diseases [2-5], which are the focus of this chapter. Tissue remodeling involving smooth muscle cells is likely to be a result of injury and dys-regulated repair processes linked to inflammation and extravascular coagulation and fibrinolysis [20-23].
3.1. Obstructive lung diseases
Obstructive lung diseases, including asthma, COPD, bronchitis and bronchiectasis, are characterized by airway obstruction. The latter is a limitation of airflow, caused by the narrowing of bronchioles. The mechano-contractile properties of the ASM cell make it the primary effecter of bronchospasm, which is an acute contraction of the airways that occurs in asthma and bronchitis. ASM cells are also involved in the array of persistent tissue structural changes of the airway wall that contribute to airway obstruction in asthma and COPD [2, 24, 25]. In airway wall remodeling (AWR), ASM cell hyperplasia, hypertrophy and changes in production of ECM protein contribute to an increase in airway wall thickness and reduction in airway wall distensibility . ASM cells in disease are major contributors to the increases in production of ECM components, including the wound type collagens, I and III, and fibronectin. ASM cells also have an important inflammatory role in airway obstructive diseases, being potent producers of growth factors, cytokines and other pro-inflammatory mediators, including granulocyte macrophage-colony stimulating factor (GM-CSF), intracellular adhesion molecule (ICAM), interleukin-1α (IL-1 α), eotaxin, leukaemia inhibitory (LIF), fractalkine and vascular cell adhesion molecule (VCAM) . Pro-inflammatory mediator expression in ASM cells is stimulated primarily by cytokines and growth factors produced by inflammatory cells and the epithelium . The ECM in the microenvironment of the ASM cell can modulate cytokine expression by ASM cells . Furthermore, cyclical changes in mechanical strain associated with breathing also modulate cytokine expression by ASM cells . As a consequence of their pivotal role in AWR, therapies that target the ASM cell are continually being explored as possible new treatments for obstructive lung diseases . Although eliminating ASM by bronchial thermoplasty is effective in reducing airway obstruction, less invasive and costly therapies are urgently needed. An effective muscle relaxing, anti-remodeling treatment that specifically targets ASM cells is expected to reduce airway reactivity and symptoms in patients with asthma or COPD [31, 32].
3.2. Vascular diseases
VSM cells reside in the medial layer of blood vessels, mediating changes in vascular tone by contracting or relaxing in response to vasoconstrictors and vasodilators respectively. In vascular injury and disease, VSM cells switch from a quiescent, contractile phenotype to a synthetic phenotype, which produces cytokines and ECM protein (
4. ECM of smooth muscle
The ECM of the smooth muscle cell microenvironment changes in injury, disease and with ageing. ECM production and modification by smooth muscle cell is regulated by intrinsic (
Collagen is the most prominent structural protein of connective tissue. Native collagen I and III form fibrils comprising supra-molecular aggregates of collagen that are stabilized by interactions between their helical domains . These fibrils have a high tensile strength that maintains the structural integrity of tissue by counter-balancing distending forces, such as those evoked by breathing on the airway wall . In the airways of patients with asthma and COPD, the ECM is expanded by fibrils of collagen I and III, including around and within smooth muscle bundles, reducing airway wall distensibility . Increased collagen, as well as ASM hyperplasia and hypertrophy, also contribute to airway wall thickening that is linked to increased airway-reactivity . In the media of the healthy blood vessel wall, collagen I and III are the main components of the ECM, with elastin also being abundant in the media of larger arterioles [42, 43]. Collagen fibrils formed by VSM cells also have an important role in fibrous cap stabilization, a stage of atherogenesis . Whilst the native forms of collagen impose mechanical strain on cells, it is the denatured forms of collagen, which perhaps are more biochemically-reactive. Increases in the activities of plasmin and MMPs, proteases which denature native collagen, occur in both respiratory  and vascular  disease. The denaturation of collagen fibrils immediately adjacent to and surrounding smooth muscle cells by pericellular proteolysis may have an important role in regulating phenotype and function in disease.
Fibronectin is a high molecular weight glycoprotein and constituent of the ECM. Fibronectin binds to the α5β1 integrin on cells to transmit biochemical and mechanical signals, and is a nucleator of fibrillogenesis
Extravascular accumulation of fibrin, formed by the coagulation cascade, occurs in a number of diseases, including respiratory and vascular diseases [21, 51-55]. Increased vascular permeability allows blood-circulating hemostatic factors such as factor VII (FVII), factor X (FX) and plasminogen to enter damaged and inflamed tissue to become activated and participate in coagulation and fibrinolysis (Figure 1).
Abundant extravascular fibrin is a specific hallmark of lung disease including asthma, and is thought to be a result of hyper-coagulation and suppressed fibrinolysis (
The medial layer of blood vessels, where VSM cells are prominent in number, is exposed to plasma exudate, even under normal physiological conditions. Whilst fibrin is present in normal arterial intima, its levels are increased in atherosclerotic lesions, particularly early proliferative, gelatinous-lesions . Again, hypercoaulation and suppressed fibrinolysis are likely to contribute to increased fibrin formation in the vasculature in disease. The coagulant, tissue factor (TF), is highly expressed in VSM cells during atherogenesis , being rapidly induced by growth factors and cytokines . Hypoxia, a driver of PAH, induces the up-regulation of PAI-1 in pulmonary artery VSM cells . In injury and disease, the deposition of fibrin into the ECM serves as a scaffold to support smooth muscle cell migration . Furthermore, fibrin degradation products (FDPs) formed by fibrinolysis, stimulate production of pro-inflammatory mediators (
Proteoglycans are another important component of the ECM synthesized by smooth muscle cells in disease including VSM cells during atherogenesis [42, 43] and ASM cells in asthma . In atherogenesis, sulphated proteoglycans, via ionic interactions with ApoB100 and ApoE, entrap low-density lipoprotein (LDL) within the vessel wall. Bound oxidized-LDL augments macrophage lipid uptake and foam cell formation, and stimulates VSM cells to secrete greater amounts of sulphated proteoglycans .
5. ECM remodeling by smooth muscle cells
Asides from producing ECM protein, smooth muscle cells also modulate the structure and form of the ECM. Extracellular modification of ECM protein involves integrins and enzymes which proteolyze and cross-link collagen. The serine protease, plasmin, also has the ability to directly activate smooth muscle cells via receptor based mechanisms. Major modifications of ECM protein by smooth muscle cells are described below:
Smooth muscle cells including VSM  and ASM  cells polymerize collagen fibrils into larger supramolecular collagen assemblies. Collagen fibrils can vary greatly in diameter (20-500 nm) and form different supramolecular structures such as bundles, weaves, and layers to suit differing roles and functions. The ability of smooth muscle cells to increase the diameter of fibrils would increase the tensile strength and resistance of the fibrils to collagenolysis by MMPs. Collagen fibrillogenesis involves integrin binding (
Matrix metalloproteases (MMPs) and plasmin are proteases involved in the degradation of ECM proteins such as fibronectin and denatured collagen. Plasmin also cleaves and activates the zymogen forms of MMPs including the MMP collagenases (MMP-1, MMP-13 and MMP-14), which denature collagen fibrils . MMPs including MMP-1, MMP-2, MMP-12 and MMP-14 are expressed by human ASM cells
Interestingly uPA and plasminogen gene deletion (but not tPA gene deletion) also reduces hypoxia-induced PAH and pulmonary vascular remodeling in mice . These effects are likely to be independent of fibrinolysis, as uPA does not bind fibrin with the same high affinity as tPA. Plasmin formed by uPA has pro-inflammatory and -remodeling activities which are not associated with the break-down of fibrin. Furthermore, uPA has plasmin(ogen)-independent effects. The amino-terminal fragment of uPA interacts with its receptor, uPAR to activate other receptors such as the formyl-peptide receptor 2 (FPR2)  and the epidermal growth factor receptor (EGFR) , to regulate migration, chemotaxis and cytokine production. uPA binding also regulates the affinity of uPAR for the α3β1-integrin , to regulate cell adhesion and cell signaling. Furthermore, the kringle domain of uPA interacts with the αvβ1-integrin in an uPAR-independent manner . Increases in the levels of uPA are associated with a number of pathologies, including asthma, COPD and PAH [59, 60, 80-82]. For smooth muscle cells, plasminogen activation by uPA is accelerated by the annexin A2 hetero-tetramer (AIIt) , an extracellular protein complex comprised of annexin A2 and S100A10 (p11). The AIIt also serves as a signal transducer for plasmin in mediating its pro-inflammatory effects on ASM cells  and macrophages . The importance of annexin A2 in cancer is becoming increasingly recognised, however, little is still known about the role of annexin A2 in respiratory disease [86-90].
The proteolytic activity of plasmin releases the otherwise latent forms of growth factors such as epidermal growth factor (EGF) and TGF-β [91, 92]. Plasminogen activation by smooth muscle cells is associated with MMP activation  and targeting the EGF-receptor (EGFR) or MMPs attenuates plasmin(ogen)-stimulated proliferation . The effects of plasmin(ogen) on EGFR signaling are contributed by heparan sulphate proteoglycan -binding EGF (HB-EGF), an EGFR ligand, which is released from heparin by MMP-mediated proteolysis (Figure 2). Like EGFR transactivation, plasmin-stimulated mobilization of matrix-bound TGF-β contributes to collagen synthesis in smooth muscle cells in a manner involving TGF-β receptor signaling . TGF-β also stimulates ASM cell proliferation , in an indirect manner involving autocrine bFGF production .
Plasmin also activates the protease-activated receptor-1 (PAR-1), the proto-typical receptor of thrombin (and FXa). PAR-1 is expressed in inflammatory cells including, macrophages, mast cells and eosinophils [96-99], and extravascular structural cells including, smooth muscle cells . Activation of PAR-1 in stromal cells is considered to evoke pro-tissue remodeling activities, which contributes to disease pathology. Levels of PARs are increased in structural cells in tissue remodeling lung diseases , and targeting PAR-1 reduces pulmonary inflammation and tissue remodeling in mouse models of lung injury and disease, including asthma [98, 102, 103]. Furthermore, PAR-1 activation elicits increased cytokine and collagen expression [103-105] and proliferation  of lung stromal cells, including ASM cells . The up-regulation of both PAR-1 and PAR-2 in VSM cells following injury and their subsequent activation by hemostatic proteases is considered to contribute to the pathogenesis of atherosclerosis . Whilst plasmin has ~10 times less affinity for PAR-1 than thrombin , integrin co-receptors augment plasmin-evoked PAR-1 activation . Binding to α9β1 integrin localizes plasmin to the cell surface and protects it from α2-antiplasmin inhibition, increasing PAR-1 activation, whilst also activating pathways downstream of α9β1 integrin through integrin-linked kinase (ILK) . Additionally to plasmin, the plasmin-activated MMP-1 and MMP-13 also cleave the N-terminal exodomain of PAR-1, but at sites alternative to those of thrombin, FXa and plasmin, eliciting distinct cellular responses .
Dysregulated matrix cross-linking and stability contributes to tissue remodeling in vascular disease and ageing. Lysyl oxidases cross-link collagen fibrils by modification of the ε-amino group in the side chain of lysines. Lysyl oxidase activity is increased in the vascular lesions of patients with PAH . The expression of lysyl oxidases in VSM cells is responsive to hypoxia and increases in the lungs of mice in experimental PAH . Glycation of collagens also induces covalent bridges between collagen fibrils, an age-related modification that contributes to arterial stiffness . Similarly, vascular calcification, which involves transglutaminase-2-induced collagen crosslinking and dimerization of osteopontin, is a degenerative and end-stage process of atherosclerosis, which also contributes to the stiffness of ageing arteries . Vascular calcification involves the de-differentiation of the VSM cell to a pro-calcificatory phenotype, where expression of the matrix Gla protein (MGP) and bone morphogenetic protein-2 (BMP-2) are decreased and increased respectively.
6. Smooth muscle cell and ECM interactions
Smooth muscle cells are highly sensitive to the biochemical and mechanical state of the surrounding ECM. Signal transduction, and the transmission and distribution of mechanical forces within the cell are dependent on the actin-cytoskeleton. This deformable polymer network also has important roles in maintaining cell shape (size) and cell migration . The interaction of the actin-cytoskeleton with the contractile apparatus and the ECM involves integrins and focal adhesion (FA) complexes, and is a key determinant of the biochemical and mechano-sensing properties of smooth muscle cells. The highly malleable actin-cytoskeleton constantly rearranges, in a process involving assembly and disassembly, in response to both bio-physical and -chemical stimuli . Alterations in smooth muscle stiffness in health and disease involve changes to actin-cytoskeleton organization, which is influenced by the ECM .
6.1. Biochemical transduction
Biochemically, ECM protein signal through integrin receptors and the dystrophin-glycoprotein complex in smooth muscle cells . The native fibrillar and denatured non-fibrillar forms of collagen regulate smooth muscle cell function differentially. The anti-proliferative effect of fibrillar collagen type I on VSM  and ASM  cells, which arrest cells in the G1 phase of the cell cycle, involves α2β1 integrin binding. Although, the non-fibrillar forms of collagen types I and III do not contribute structurally to tissue integrity, they retain cell signaling activity. The GFOGER motif of the characteristic triple helix of non-fibrillar type I collagen binds with high affinity to the integrins α1β1, α2β1, α10β1, and α11β1 . Furthermore, proteolytic cleavage of the helix by MMPs and plasmin reveals the ‘matricryptic’ RGD integrin-binding site . Non-fibrillar type I collagen stimulates smooth muscle cell proliferation , survival , and cytokine release  in an integrin-dependent manner. Similarly, fibronectin, which binds α5β1 integrin via its RGD motif, also stimulates smooth muscle cell proliferation  and augments cytokine production in response to stimuli such as IL-1β . Fibrin degradation products (FDPs) also regulate smooth muscle cell migration via binding the α5β3 integrin , as well as stimulating smooth muscle cell cytokine production and proliferation via binding TLR-4 .
Connections between the ECM and the actin cytoskeleton of smooth muscle cells allows for an efficient transfer of force between the contractile apparatus and the extracellular environment, which is important in myogenic force generation . These same connections, which involve integrins and FA complexes, also regulate smooth muscle cell stiffness and phenotype. Mechanical forces, whether external or internal to tissue in which smooth muscle cells reside, stretch and strain protein-cell surface integrin FA complexes, activating downstream intracellular signaling pathways. This process is termed mechano-transduction, and often elicits mechanically sensitive ion channels to open or close, changing the polarity of the membrane potential, which then activates voltage-gated channels. Mechanical strain in smooth muscle cells activates RhoA, a pivotal regulator of actin adhesion organization . The β1-integrin is an important mechanoreceptor, regulating cell function and viability via the inositol 3-kinase (PI3K)/Akt signaling pathway, in a process involving FA kinase (FAK) and integrin-linked kinase (ILK) phosphorylation [124, 125].
In arterial blood vessels, integrin-mediated mechano-transduction triggers intracellular Ca2+ mobilization in VSM cells to evoke myogenic responses . The integrin-mediated adhesion of VSM cells to the ECM is dynamically regulated in opposing directions by vasoconstrictors (
In disease, smooth muscle cell biology is affected by changes in the ECM, including increases in substrate stiffness and the generation of isometric forces in tethered collagen lattices, which influence mechano-transduction. In severe asthma, the “strait jacket” effect of ASM cells being embedded in a rigid microenvironment may reduce the amplitude of the oscillatory forces associated with breathing. This is likely to have potential consequences on smooth muscle biology, as has been proposed for lung fibroblasts in fibrotic foci (FF) lesions in idiopathic pulmonary fibrosis (IPF) . Tensile collagen fibrils within FF form a rigid environment that reduces the magnitude of cyclical strain the fibroblasts are normally subjected to in healthy tissue upon breathing. A reduction in the amplitude of force of breathing-associated cyclical strain is thought to increase lung fibroblast fibrogenic activity and stiffness.
6.3. Interconnection of biochemical- and mechanical-evoked signaling
ECM biochemistry and mechanics are very much interconnected in their regulation of smooth muscle behavior. The influence of mechanics on smooth muscle cell biology is modulated by ligand biochemistry. For example, smooth muscle cells grown on fibronectin, as compared to laminin, exhibit increased cell adhesion and cytoskeletal polymerization in response to increasing stiffness of the substrata,
7. Targeting smooth muscle cell biology as therapy
Strategies that target smooth muscle cell biology, including ECM-smooth muscle cell interactions, may be beneficial in the treatment of tissue remodeling diseases. Approaches that target proteases, which modulate the ECM or ECM-signaling of smooth muscle cells in disease, will be of particular focus in this chapter section.
7.1. Contractile, hypertrophic and hyperplasic regulators
Targeting factors which regulate smooth muscle contractility, hyperplasia and/or hypertrophy are currently used in the treatment of airway and vascular diseases. β2-Adrenergic receptor agonists, which increase the intracellular second messenger, cyclic AMP (cAMP), in ASM cells, are used pharmacologically to dampen bronchoconstriction in asthma and COPD . Blockade of endothelin (ET) receptors are an effective treatment for PAH. Endothelin-1 (ET-1) is both a vasoconstrictor and mitogen, evoking its effects on VSM cells through binding to ETA or ETB receptors. Another treatment of PAH is prostacyclin (or its analogs), an eicosanoid, which like the prostaglandins and thromboxane, is vasodilatory . Eicosanoids, which are released by endothelial cells, stimulate increases in the levels of intracellular cAMP in VSM cells via binding prostanoid/G-protein coupled receptors. Increases in cAMP inhibit myosin light chain phosphorylation, causing relaxation, as well as inhibiting proliferation . Similarly, the endogenous vasodilator nitric oxide (NO), which is released by endothelial cells, also inhibits both myosin light chain phosphorylation (via increases in cGMP) and proliferation of VSM cells . Various NO donors such as glycerine trinitrate and sodium nitroprusside (SNP) have been used in the treatment of vascular disease and endothelial dysfunction (
7.2. Growth factors
Growth factors such as PDGF, TGF-β and VEGF which regulate smooth muscle proliferation and size, may also be potential targets for the treatment of vascular and lung obstructive diseases . Imatinib, a receptor tyrosine kinase inhibitor which inhibits PDGF signaling, attenuates both VSM cell hyperplasia and hypertrophy in pre-clinical models of vascular disease . However, imatinib was withdrawn from clinical trials for the treatment of advanced PAH, because of serious side effects and increased morbidity . Inhibiting specific aspects of TGF-β signaling may be another growth factor-targeting strategy to treat tissue remodeling in disease. Aberrant TGF-β signaling, important in regulating smooth muscle function including cell stiffness and proliferation [141, 142], contributes to tissue remodeling in vascular and respiratory diseases [143-145]. The TGF-β superfamily member, activin A, is linked with the progression of PAH, stimulating VSM cell proliferation . Administration of follistatin, an endogenous inhibitor of activin A, attenuates inflammation and remodeling in experimental models of lung injury and disease .
Targeting proteases that modify smooth muscle ECM structure and its biomechanical properties are another strategy to treat vascular and obstructive lung disease. Inhibition of pericellular collagenolysis
(annexin A2 knockout)
|Allergen||Reduced airway inflammation .|
|Allergen||Reduced AWR. Administered after AWR was established .|
|Arterial injury||Reduced perturbations to right ventricular systolic pressure, right ventricular hypertrophy, and vessel muscularization and normalized collagen cross-linking and vessel matrix architecture|
|Allergen||Reduced airway hyper-responsiveness .|
|APT||Reduced hypertension and right ventricular dysfunction .|
(tranexamic acid) and genetic (plasminogen knockout)
|Allergen||Reduced eosinophil and lymphocyte numbers, mucus production, and collagen deposition in the lungs .|
|Bleomycin||Reduced alveolar macrophage / Increased lung collagen .|
|Hypoxia||Reduced pulmonary hypertension and pulmonary vascular remodeling .|
|Hypoxia||No effect .|
|PAI-1||Pharmacological (IMD-1622)||Arterial injury||Reduced arterial neointimal formation, increases in adhesion molecules, fibrinogen accumulation |
|PAI-1||Genetic (PAI-1 knockout)||Allergen||Reduced AWR including sub-epithelial fibrosis [61, 62].|
|PAI-1||Genetic (PAI-1 knockout)||Bleomycin||Reduced lung collagen .|
|PAI-1||Pharmacological (Tiplaxtinin)||Allergen||Reduced AWR |
|PAI-1||Genetic (PAI-1 knockout)||Endotoxin||Reduced neutrophil recruitment to the lungs  and fibrin deposition and AWR in the airways .|
|PAI-1||Genetic (PAI-1 knockout)||Arterial injury||Reduced arterial neointimal formation .|
|Allergen||Reduced AWR .|
|PAR-1||Genetic (PAR-1 knockout)||Bleomycin||Reduced collagen accumulation in lung and pulmnonary inflammation .|
|PAR-1||Pharmacological (Atopaxar)||APT||Reduced neointimal thickening in arterial blood vessels |
|PAR-1||Pharmacological (F16618)||Balloon angioplasty||Reduced restenosis |
|tPA||Therapeutic (nebulized tPA)||Allergen||Reduced airway hyper-responsiveness |
|tPA||Genetic (tPA knockout)||Bleomycin||Increased lung collagen/ alveolar hemorrhage .|
|tPA||Genetic (tPA knockout)||Hypoxia||Had no effect on pulmonary hypertension or pulmonary vascular remodeling .|
|uPA||Therapeutic (anti-uPA antibodies)||Endotoxin||Reduced inflammation and edema |
|uPA||Genetic (uPA knockout)||Bleomycin||Reduced alveolar macrophages .|
|uPA||Genetic (uPA knockout)||Endotoxin||Reduced lung edema, pulmonary neutrophil accumulation, and pro-inflammatory cytokine levels .|
|uPA||Genetic (uPA knockout)||Hypoxia||Reduced pulmonary hypertension and pulmonary vascular remodeling .|
|uPAR||Genetic (uPAR knockout)||Bleomycin||Reduced alveolar macrophages .|
Reducing the accumulation of extravascular fibrin in damaged tissue would be expected to reduce tissue remodeling in disease. Anti-coagulants are already used in the treatment of vascular disease to reduce thrombosis by disrupting hemostasis. Whilst clinical asthma trials with nebulized heparin have provided mixed results , systemic administration of
The coagulants FXa and thrombin may also contribute to tissue remodeling via their activation of PAR-1 on stromal cells including ASM and VSM cells. PAR-1 antagonists reduce AWR in a murine model of chronic allergic airway inflammation  and pulmonary inflammation and fibrosis in mice following bleomycin-induced lung injury [102, 103] (table 1). Similarly PAR-1 antagonists reduce restenosis  and intimal thickening  in the vascular wall following balloon injury
7.5. Fibrinolytic agents
Potential therapies that reduce fibrin by using fibrinolytic agents, have been considered in the treatment of lung disease for some time . Thrombolytic therapy using tPA-mimetics are already used for stroke and myocardial infarction, despite a higher risk of bleeding complications . A potential strategy to treat asthma is to augment airspace fibrinolysis. Tiplaxtinin, a small molecule inhibitor of PAI-1 , or inhaled tPA , attenuate AWR or reactivity in allergen-challenged mice (table 1). In animal studies of vascular injury and disease, PAI-1 inhibitors  or PAI-1 gene deletion  reduced neointima formation.
7.6. uPA and annexin A2
Both uPA and annexin A2 may be potential novel drug targets in the treatment of chronic respiratory disease . Both uPA and annexin A2 gene-deletion reduces pulmonary inflammation in various murine models [84, 150, 160], and uPA antibodies reduce inflammation and edema in a mouse model of acute lung injury  (table 1). However, further pre-clinical characterization of these inhibitors as therapy for tissue remodeling diseases is required. The roles of uPA and annexin A2 in cancer are well established, and their targeting by either pharmacological or antibody-based therapies have been shown to reduce tumour growth and/or metastasis in a number of pre-clinical cancer models [86-90]. Furthermore, clinical trials for cancer have shown uPA inhibitors are well tolerated in humans and have generated promising results .
7.7. Cross-linking enzymes
As the expression of lysyl oxidases are dysregulated in PAH, modulation of lung matrix cross-linking may limit pulmonary vascular remodeling associated with PAH. In support, β-aminopropionitrile, an inhibitor of lysyl oxidase, attenuates the effect of hypoxia on vascular remodeling in experimental PAH  (table 1).
Cytoskeletal changes in smooth muscle cells occur in association with increases in stiffness (
Understanding the molecular mechanisms by which the ECM regulates smooth muscle cell function in disease remains a key challenge to developing effective therapeutics for managing tissue remodeling diseases such as obstructive lung and vascular diseases. Insight into the biology of the smooth muscle cell in these diseases has increased rapidly in the recent years, leading to the concept that successful strategies for managing tissue remodeling may include restoring smooth muscle phenotype. Such approaches could possibly involve modulating the ECM of the smooth muscle microenvironment, or the factors which are involved in the transmission of the biochemical and biomechanical properties of the ECM. Proteases of the coagulation and plasminogen activation systems are of particular interest as therapeutic targets, as they not only have roles in forming and modifying ECM, but also can directly stimulate changes in smooth muscle cell function and phenotype. The challenge is to target these proteases without disrupting their roles in hemostasis, in order to avoid bleeding complications.
Funding support: NHMRC (Australia) research grant APP1022048.
Chiba Y, Misawa M. The role of RhoA-mediated Ca2+ sensitization of bronchial smooth muscle contraction in airway hyperresponsiveness. J Smooth Muscle Res. 2004;40(4-5]):155-67. Epub 2005/01/19.
James AL, Wenzel S. Clinical relevance of airway remodelling in airway diseases. The European respiratory journal. 2007;30(1]):134-55. Epub 2007/07/03.
Decramer M, Janssens W, Miravitlles M. Chronic obstructive pulmonary disease. Lancet. 2012;379(9823]):1341-51. Epub 2012/02/09.
Hopkins N, McLoughlin P. The structural basis of pulmonary hypertension in chronic lung disease: remodelling, rarefaction or angiogenesis? J Anat. 2002;201(4]):335-48. Epub 2002/11/15.
Martorell L, Martinez-Gonzalez J, Rodriguez C, Gentile M, Calvayrac O, Badimon L. Thrombin and protease-activated receptors (PARs) in atherothrombosis. Thrombosis and haemostasis. 2008;99(2]):305-15. Epub 2008/02/19.
Ha YM, Lee DH, Kim M, Kang YJ. High glucose induces connective tissue growth factor expression and extracellular matrix accumulation in rat aorta vascular smooth muscle cells via extracellular signal-regulated kinase 1/2. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology. 2013;17(4]):307-14. Epub 2013/08/16.
Taubman MB, Wang L, Miller C. The role of smooth muscle derived tissue factor in mediating thrombosis and arterial injury. Thrombosis research. 2008;122 Suppl 1:S78-81. Epub 2008/08/12.
Hou Y, Okamoto C, Okada K, Kawao N, Kawata S, Ueshima S, et al. c-Myc is essential for urokinase plasminogen activator expression on hypoxia-induced vascular smooth muscle cells. Cardiovascular research. 2007;75(1]):186-94. Epub 2007/03/27.
Nave AH, Mizikova I, Niess G, Steenbock H, Reichenberger F, Talavera ML, et al. Lysyl oxidases play a causal role in vascular remodeling in clinical and experimental pulmonary arterial hypertension. Arteriosclerosis, thrombosis, and vascular biology. 2014;34(7]):1446-58. Epub 2014/05/17.
Koziol-White CJ, Panettieri RA, Jr. Airway smooth muscle and immunomodulation in acute exacerbations of airway disease. Immunol Rev. 2011;242(1]):178-85. Epub 2011/06/21.
Ward JE, Harris T, Bamford T, Mast A, Pain MC, Robertson C, et al. Proliferation is not increased in airway myofibroblasts isolated from asthmatics. The European respiratory journal. 2008;32(2]):362-71.
Flavell SJ, Hou TZ, Lax S, Filer AD, Salmon M, Buckley CD. Fibroblasts as novel therapeutic targets in chronic inflammation. Br J Pharmacol. 2008;153 Suppl 1:S241-6. Epub 2007/10/30.
Li M, Riddle SR, Frid MG, El Kasmi KC, McKinsey TA, Sokol RJ, et al. Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension. J Immunol. 2011;187(5]):2711-22. Epub 2011/08/05.
Alkhouri H, Poppinga WJ, Tania NP, Ammit A, Schuliga M. Regulation of pulmonary inflammation by mesenchymal cells. Pulmonary pharmacology & therapeutics. 2014;29(2]):156-65. Epub 2014/03/25.
Crosswhite P, Sun Z. Molecular mechanisms of pulmonary arterial remodeling. Mol Med. 2014;20:191-201. Epub 2014/03/29.
Ito S, Majumdar A, Kume H, Shimokata K, Naruse K, Lutchen KR, et al. Viscoelastic and dynamic nonlinear properties of airway smooth muscle tissue: roles of mechanical force and the cytoskeleton2006 2006-06-01 00:00:00. L1227-L37 p.
Rattan S. The internal anal sphincter: regulation of smooth muscle tone and relaxation. Neurogastroenterology & Motility. 2005;17:50-9.
Lang RJ, Tonta MA, Zoltkowski BZ, Meeker WF, Wendt I, Parkington HC. Pyeloureteric peristalsis: role of atypical smooth muscle cells and interstitial cells of Cajal-like cells as pacemakers. The Journal of physiology. 2006;576(Pt 3]):695-705. Epub 2006/09/02.
Webb RC. Smooth muscle contraction and relaxation. Advances in physiology education. 2003;27(1-4]):201-6. Epub 2003/11/25.
Holgate ST, Holloway J, Wilson S, Howarth PH, Haitchi HM, Babu S, et al. Understanding the pathophysiology of severe asthma to generate new therapeutic opportunities. The Journal of allergy and clinical immunology. 2006;117(3]):496-506; quiz 7. Epub 2006/03/09.
Smith EB. Fibrinogen, fibrin and the arterial wall. European heart journal. 1995;16 Suppl A:11-4; discussion 4-5. Epub 1995/03/01.
Fay WP, Garg N, Sunkar M. Vascular functions of the plasminogen activation system. Arterioscler Thromb Vasc Biol. 2007;27(6]):1231-7. Epub 2007/03/24.
Levin EG, Loskutoff DJ. Comparative studies of the fibrinolytic activity of cultured vascular cells. Thrombosis research. 1979;15(5-6]):869-78. Epub 1979/01/01.
Amin K, Ludviksdottir D, Janson C, Nettelbladt O, Bjornsson E, Roomans GM, et al. Inflammation and structural changes in the airways of patients with atopic and nonatopic asthma. BHR Group. American journal of respiratory and critical care medicine. 2000;162(6]):2295-301. Epub 2000/12/09.
Gosselink JV, Hayashi S, Elliott WM, Xing L, Chan B, Yang L, et al. Differential expression of tissue repair genes in the pathogenesis of chronic obstructive pulmonary disease. American journal of respiratory and critical care medicine. 2010;181(12]):1329-35. Epub 2010/01/16.
Wilson JW, Li X, Pain MC. The lack of distensibility of asthmatic airways. Am Rev Respir Dis. 1993;148(3]):806-9. Epub 1993/09/01.
Xia YC, Redhu NS, Moir LM, Koziol-White C, Ammit AJ, Al-Alwan L, et al. Pro-inflammatory and immunomodulatory functions of airway smooth muscle: emerging concepts. Pulmonary pharmacology & therapeutics. 2013;26(1]):64-74. Epub 2012/05/29.
Peng Q, Lai D, Nguyen TT, Chan V, Matsuda T, Hirst SJ. Multiple beta 1 integrins mediate enhancement of human airway smooth muscle cytokine secretion by fibronectin and type I collagen. J Immunol. 2005;174(4]):2258-64. Epub 2005/02/09.
Bonacci JV, Harris T, Stewart AG. Impact of extracellular matrix and strain on proliferation of bovine airway smooth muscle. Clinical and experimental pharmacology & physiology. 2003;30(5-6]):324-8. Epub 2003/07/16.
Camoretti-Mercado B. Targeting the airway smooth muscle for asthma treatment. Translational research : the journal of laboratory and clinical medicine. 2009;154(4]):165-74. Epub 2009/09/22.
Redington AE. Airway fibrosis in asthma: mechanisms, consequences, and potential for therapeutic intervention. Monaldi Arch Chest Dis. 2000;55(4]):317-23. Epub 2000/11/01.
Stewart AG, Tomlinson PR, Wilson J. Airway wall remodelling in asthma: a novel target for the development of anti-asthma drugs. Trends Pharmacol Sci. 1993;14(7]):275-9. Epub 1993/07/01.
Doran AC, Meller N, McNamara CA. Role of smooth muscle cells in the initiation and early progression of atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology. 2008;28(5]):812-9. Epub 2008/02/16.
Lacolley P, Regnault V, Nicoletti A, Li Z, Michel JB. The vascular smooth muscle cell in arterial pathology: a cell that can take on multiple roles. Cardiovascular research. 2012;95(2]):194-204. Epub 2012/04/03.
Pak O, Aldashev A, Welsh D, Peacock A. The effects of hypoxia on the cells of the pulmonary vasculature. The European respiratory journal. 2007;30(2]):364-72. Epub 2007/08/02.
Crosswhite P, Sun Z. Nitric oxide, oxidative stress and inflammation in pulmonary arterial hypertension. J Hypertens. 2010;28(2]):201-12. Epub 2010/01/07.
Schabbauer G, Matt U, Gunzl P, Warszawska J, Furtner T, Hainzl E, et al. Myeloid PTEN promotes inflammation but impairs bactericidal activities during murine pneumococcal pneumonia. J Immunol. 2010;185(1]):468-76. Epub 2010/05/28.
Horita H, Furgeson SB, Ostriker A, Olszewski KA, Sullivan T, Villegas LR, et al. Selective inactivation of PTEN in smooth muscle cells synergizes with hypoxia to induce severe pulmonary hypertension. J Am Heart Assoc. 2013;2(3]):e000188. Epub 2013/06/04.
Fixman ED, Stewart A, Martin JG. Basic mechanisms of development of airway structural changes in asthma. The European respiratory journal. 2007;29(2]):379-89.
van der Rest M, Garrone R. Collagen family of proteins. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 1991;5(13]):2814-23. Epub 1991/10/01.
Dunsmore SE, Rannels DE. Extracellular matrix biology in the lung. The American journal of physiology. 1996;270(1 Pt 1]):L3-27. Epub 1996/01/01.
Newby AC, Zaltsman AB. Fibrous cap formation or destruction--the critical importance of vascular smooth muscle cell proliferation, migration and matrix formation. Cardiovascular research. 1999;41(2]):345-60. Epub 1999/05/26.
Wagenseil JE, Mecham RP. Elastin in large artery stiffness and hypertension. Journal of cardiovascular translational research. 2012;5(3]):264-73. Epub 2012/02/01.
Leitinger N. "Obese" smooth muscle cells fail to assemble collagen fibrils. Circulation research. 2009;104(7]):826-8. Epub 2009/04/11.
Oikonomidi S, Kostikas K, Tsilioni I, Tanou K, Gourgoulianis KI, Kiropoulos TS. Matrix metalloproteinases in respiratory diseases: from pathogenesis to potential clinical implications. Current medicinal chemistry. 2009;16(10]):1214-28. Epub 2009/04/10.
Araujo BB, Dolhnikoff M, Silva LF, Elliot J, Lindeman JH, Ferreira DS, et al. Extracellular matrix components and regulators in the airway smooth muscle in asthma. The European respiratory journal. 2008;32(1]):61-9. Epub 2008/03/07.
Chan V, Burgess JK, Ratoff JC, O'Connor B J, Greenough A, Lee TH, et al. Extracellular matrix regulates enhanced eotaxin expression in asthmatic airway smooth muscle cells. American journal of respiratory and critical care medicine. 2006;174(4]):379-85. Epub 2006/05/20.
Kuo C, Lim S, King NJ, Johnston SL, Burgess JK, Black JL, et al. Rhinovirus infection induces extracellular matrix protein deposition in asthmatic and nonasthmatic airway smooth muscle cells. American journal of physiology Lung cellular and molecular physiology. 2011;300(6]):L951-7. Epub 2011/04/05.
Vogel ER, VanOosten SK, Holman MA, Hohbein DD, Thompson MA, Vassallo R, et al. Cigarette smoke enhances proliferation and extracellular matrix deposition by human fetal airway smooth muscle. American journal of physiology Lung cellular and molecular physiology. 2014;307(12]):L978-86. Epub 2014/10/26.
Moir LM, Burgess JK, Black JL. Transforming growth factor beta 1 increases fibronectin deposition through integrin receptor alpha 5 beta 1 on human airway smooth muscle. The Journal of allergy and clinical immunology. 2008;121(4]):1034-9 e4. Epub 2008/02/05.
Tucker T, Idell S. Plasminogen-plasmin system in the pathogenesis and treatment of lung and pleural injury. Seminars in thrombosis and hemostasis. 2013;39(4]):373-81. Epub 2013/03/19.
Wagers SS, Norton RJ, Rinaldi LM, Bates JH, Sobel BE, Irvin CG. Extravascular fibrin, plasminogen activator, plasminogen activator inhibitors, and airway hyperresponsiveness. The Journal of clinical investigation. 2004;114(1]):104-11. Epub 2004/07/03.
Noble PW, Barkauskas CE, Jiang D. Pulmonary fibrosis: patterns and perpetrators. The Journal of clinical investigation. 2012;122(8]):2756-62. Epub 2012/08/02.
Raghu H, Flick MJ. Targeting the coagulation factor fibrinogen for arthritis therapy. Current pharmaceutical biotechnology. 2011;12(9]):1497-506. Epub 2011/03/16.
Schardt FW, Schmausser B, Bachmann E. Monoclonal antibodies for immunodectection of fibrin deposits on cancer cells. Histology and histopathology. 2013;28(8]):993-8. Epub 2013/02/02.
Kim J, Hajjar KA. Annexin II: a plasminogen-plasminogen activator co-receptor. Front Biosci. 2002;7:d341-8. Epub 2002/01/30.
Madureira PA, Surette AP, Phipps KD, Taboski MA, Miller VA, Waisman DM. The role of the annexin A2 heterotetramer in vascular fibrinolysis. Blood. 2011;118(18]):4789-97. Epub 2011/09/13.
Brims FJ, Chauhan AJ, Higgins B, Shute JK. Coagulation factors in the airways in moderate and severe asthma and the effect of inhaled steroids. Thorax. 2009;64(12]):1037-43. Epub 2009/08/26.
Kowal K, Zukowski S, Moniuszko M, Bodzenta-Lukaszyk A. Plasminogen activator inhibitor-1 (PAI-1]) and urokinase plasminogen activator (uPA) in sputum of allergic asthma patients. Folia Histochem Cytobiol. 2008;46(2]):193-8. Epub 2008/06/04.
Xiao W, Hsu YP, Ishizaka A, Kirikae T, Moss RB. Sputum cathelicidin, urokinase plasminogen activation system components, and cytokines discriminate cystic fibrosis, COPD, and asthma inflammation. Chest. 2005;128(4]):2316-26. Epub 2005/10/21.
Kuramoto E, Nishiuma T, Kobayashi K, Yamamoto M, Kono Y, Funada Y, et al. Inhalation of urokinase-type plasminogen activator reduces airway remodeling in a murine asthma model. American journal of physiology Lung cellular and molecular physiology. 2009;296(3]):L337-46. Epub 2008/12/23.
Oh CK, Ariue B, Alban RF, Shaw B, Cho SH. PAI-1 promotes extracellular matrix deposition in the airways of a murine asthma model. Biochemical and biophysical research communications. 2002;294(5]):1155-60. Epub 2002/06/21.
Dimova EY, Samoylenko A, Kietzmann T. Oxidative stress and hypoxia: implications for plasminogen activator inhibitor-1 expression. Antioxid Redox Signal. 2004;6(4]):777-91. Epub 2004/07/10.
Naito M, Stirk CM, Smith EB, Thompson WD. Smooth muscle cell outgrowth stimulated by fibrin degradation products. The potential role of fibrin fragment E in restenosis and atherogenesis. Thrombosis research. 2000;98(2]):165-74. Epub 2000/03/14.
Guo F, Liu J, Wang C, Liu N, Lu P. Fibrinogen, fibrin, and FDP induce C-reactive protein generation in rat vascular smooth muscle cells: pro-inflammatory effect on atherosclerosis. Biochemical and biophysical research communications. 2009;390(3]):942-6. Epub 2009/10/27.
Parameswaran K, Willems-Widyastuti A, Alagappan VK, Radford K, Kranenburg AR, Sharma HS. Role of extracellular matrix and its regulators in human airway smooth muscle biology. Cell biochemistry and biophysics. 2006;44(1]):139-46. Epub 2006/02/04.
Li S, Van Den Diepstraten C, D'Souza SJ, Chan BM, Pickering JG. Vascular smooth muscle cells orchestrate the assembly of type I collagen via alpha2beta1 integrin, RhoA, and fibronectin polymerization. The American journal of pathology. 2003;163(3]):1045-56. Epub 2003/08/26.
Schuliga M, Ong SC, Soon L, Zal F, Harris T, Stewart AG. Airway smooth muscle remodels pericellular collagen fibrils: implications for proliferation. American journal of physiology Lung cellular and molecular physiology. 2010;298(4]):L584-92. Epub 2010/01/19.
Velling T, Risteli J, Wennerberg K, Mosher DF, Johansson S. Polymerization of type I and III collagens is dependent on fibronectin and enhanced by integrins alpha 11beta 1 and alpha 2beta 1. The Journal of biological chemistry. 2002;277(40]):37377-81. Epub 2002/07/30.
Frontini MJ, O'Neil C, Sawyez C, Chan BM, Huff MW, Pickering JG. Lipid incorporation inhibits Src-dependent assembly of fibronectin and type I collagen by vascular smooth muscle cells. Circulation research. 2009;104(7]):832-41. Epub 2009/02/21.
Deryugina EI, Quigley JP. Cell surface remodeling by plasmin: a new function for an old enzyme. J Biomed Biotechnol. 2012;2012:564259. Epub 2012/10/26.
Xie S, Issa R, Sukkar MB, Oltmanns U, Bhavsar PK, Papi A, et al. Induction and regulation of matrix metalloproteinase-12 in human airway smooth muscle cells. Respiratory research. 2005;6:148. Epub 2005/12/20.
Schuliga M, Harris T, Stewart AG. Plasminogen activation by airway smooth muscle is regulated by type I collagen. American journal of respiratory cell and molecular biology. 2011;44(6]):831-9. Epub 2010/08/10.
Swaisgood CM, Aronica MA, Swaidani S, Plow EF. Plasminogen is an important regulator in the pathogenesis of a murine model of asthma. American journal of respiratory and critical care medicine. 2007;176(4]):333-42. Epub 2007/06/02.
Levi M, Moons L, Bouche A, Shapiro SD, Collen D, Carmeliet P. Deficiency of urokinase-type plasminogen activator-mediated plasmin generation impairs vascular remodeling during hypoxia-induced pulmonary hypertension in mice. Circulation. 2001;103(15]):2014-20. Epub 2001/04/18.
de Paulis A, Montuori N, Prevete N, Fiorentino I, Rossi FW, Visconte V, et al. Urokinase induces basophil chemotaxis through a urokinase receptor epitope that is an endogenous ligand for formyl peptide receptor-like 1 and -like 2. J Immunol. 2004;173(9]):5739-48. Epub 2004/10/21.
Bakken AM, Protack CD, Roztocil E, Nicholl SM, Davies MG. Cell migration in response to the amino-terminal fragment of urokinase requires epidermal growth factor receptor activation through an ADAM-mediated mechanism. J Vasc Surg. 2009;49(5]):1296-303. Epub 2009/04/28.
Wei Y, Eble JA, Wang Z, Kreidberg JA, Chapman HA. Urokinase receptors promote beta1 integrin function through interactions with integrin alpha3beta1. Mol Biol Cell. 2001;12(10]):2975-86. Epub 2001/10/13.
Tarui T, Akakura N, Majumdar M, Andronicos N, Takagi J, Mazar AP, et al. Direct interaction of the kringle domain of urokinase-type plasminogen activator (uPA) and integrin alpha v beta 3 induces signal transduction and enhances plasminogen activation. Thrombosis and haemostasis. 2006;95(3]):524-34. Epub 2006/03/10.
Brims FJ, Chauhan AJ, Higgins B, Shute JK. Up-regulation of the extrinsic coagulation pathway in acute asthma--a case study. J Asthma. 2010;47(6]):695-8. Epub 2010/07/10.
Shetty S, Bhandary YP, Shetty SK, Velusamy T, Shetty P, Bdeir K, et al. Induction of tissue factor by urokinase in lung epithelial cells and in the lungs. American journal of respiratory and critical care medicine. 2010;181(12]):1355-66. Epub 2010/03/03.
Zhang Y, Xiao W, Jiang Y, Wang H, Xu X, Ma D, et al. Levels of components of the urokinase-type plasminogen activator system are related to chronic obstructive pulmonary disease parenchymal destruction and airway remodelling. J Int Med Res. 2012;40(3]):976-85. Epub 2012/08/22.
Stewart AG, Xia YC, Harris T, Royce S, Hamilton JA, Schuliga M. Plasminogen-stimulated airway smooth muscle cell proliferation is mediated by urokinase and annexin A2, involving plasmin-activated cell signalling. Br J Pharmacol. 2013;170(7]):1421-35. Epub 2013/10/12.
Schuliga M, Langenbach S, Xia YC, Qin C, Mok JS, Harris T, et al. Plasminogen-stimulated inflammatory cytokine production by airway smooth muscle cells is regulated by annexin A2. American journal of respiratory cell and molecular biology. 2013;49(5]):751-8. Epub 2013/06/01.
Li Q, Laumonnier Y, Syrovets T, Simmet T. Plasmin triggers cytokine induction in human monocyte-derived macrophages. Arteriosclerosis, thrombosis, and vascular biology. 2007;27(6]):1383-9. Epub 2007/04/07.
Henneke I, Greschus S, Savai R, Korfei M, Markart P, Mahavadi P, et al. Inhibition of urokinase activity reduces primary tumor growth and metastasis formation in a murine lung carcinoma model. American journal of respiratory and critical care medicine. 2010;181(6]):611-9. Epub 2010/01/09.
Schmitt M, Harbeck N, Brunner N, Janicke F, Meisner C, Muhlenweg B, et al. Cancer therapy trials employing level-of-evidence-1 disease forecast cancer biomarkers uPA and its inhibitor PAI-1. Expert Rev Mol Diagn. 2011;11(6]):617-34. Epub 2011/07/13.
Sharma M, Blackman MR, Sharma MC. Antibody-directed neutralization of annexin II (ANX II) inhibits neoangiogenesis and human breast tumor growth in a xenograft model. Experimental and molecular pathology. 2012;92(1]):175-84. Epub 2011/11/03.
Sharma M, Ownbey RT, Sharma MC. Breast cancer cell surface annexin II induces cell migration and neoangiogenesis via tPA dependent plasmin generation. Experimental and molecular pathology. 2010;88(2]):278-86. Epub 2010/01/19.
Zheng L, Foley K, Huang L, Leubner A, Mo G, Olino K, et al. Tyrosine 23 phosphorylation-dependent cell-surface localization of annexin A2 is required for invasion and metastases of pancreatic cancer. PloS one. 2011;6(4]):e19390. Epub 2011/05/17.
Coutts A, Chen G, Stephens N, Hirst S, Douglas D, Eichholtz T, et al. Release of biologically active TGF-beta from airway smooth muscle cells induces autocrine synthesis of collagen. American journal of physiology Lung cellular and molecular physiology. 2001;280(5]):L999-1008. Epub 2001/04/06.
Roztocil E, Nicholl SM, Galaria, II, Davies MG. Plasmin-induced smooth muscle cell proliferation requires epidermal growth factor activation through an extracellular pathway. Surgery. 2005;138(2]):180-6. Epub 2005/09/13.
Chen G, Khalil N. TGF-beta1 increases proliferation of airway smooth muscle cells by phosphorylation of map kinases. Respiratory research. 2006;7:2. Epub 2006/01/05.
Bosse Y, Thompson C, Stankova J, Rola-Pleszczynski M. Fibroblast growth factor 2 and transforming growth factor beta1 synergism in human bronchial smooth muscle cell proliferation. American journal of respiratory cell and molecular biology. 2006;34(6]):746-53. Epub 2006/01/28.
Hirota N, Risse PA, Novali M, McGovern T, Al-Alwan L, McCuaig S, et al. Histamine may induce airway remodeling through release of epidermal growth factor receptor ligands from bronchial epithelial cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2012;26(4]):1704-16. Epub 2012/01/17.
Bolton SJ, McNulty CA, Thomas RJ, Hewitt CR, Wardlaw AJ. Expression of and functional responses to protease-activated receptors on human eosinophils. J Leukoc Biol. 2003;74(1]):60-8. Epub 2003/07/02.
Stenton GR, Nohara O, Dery RE, Vliagoftis H, Gilchrist M, Johri A, et al. Proteinase-activated receptor (PAR)-1 and -2 agonists induce mediator release from mast cells by pathways distinct from PAR-1 and PAR-2. The Journal of pharmacology and experimental therapeutics. 2002;302(2]):466-74. Epub 2002/07/20.
Zhu W, Bi M, Liu Y, Wang Y, Pan F, Qiu L, et al. Thrombin promotes airway remodeling via protease-activated receptor-1 and transforming growth factor-beta1 in ovalbumin-allergic rats. Inhal Toxicol. 2013;25(10]):577-86. Epub 2013/08/14.
Colognato R, Slupsky JR, Jendrach M, Burysek L, Syrovets T, Simmet T. Differential expression and regulation of protease-activated receptors in human peripheral monocytes and monocyte-derived antigen-presenting cells. Blood. 2003;102(7]):2645-52. Epub 2003/06/14.
Knight DA, Lim S, Scaffidi AK, Roche N, Chung KF, Stewart GA, et al. Protease-activated receptors in human airways: upregulation of PAR-2 in respiratory epithelium from patients with asthma. The Journal of allergy and clinical immunology. 2001;108(5]):797-803. Epub 2001/11/03.
Mercer PF, Johns RH, Scotton CJ, Krupiczojc MA, Konigshoff M, Howell DC, et al. Pulmonary epithelium is a prominent source of proteinase-activated receptor-1-inducible CCL2 in pulmonary fibrosis. American journal of respiratory and critical care medicine. 2009;179(5]):414-25. Epub 2008/12/09.
Howell DC, Johns RH, Lasky JA, Shan B, Scotton CJ, Laurent GJ, et al. Absence of proteinase-activated receptor-1 signaling affords protection from bleomycin-induced lung inflammation and fibrosis. The American journal of pathology. 2005;166(5]):1353-65. Epub 2005/04/28.
Scotton CJ, Krupiczojc MA, Konigshoff M, Mercer PF, Lee YC, Kaminski N, et al. Increased local expression of coagulation factor X contributes to the fibrotic response in human and murine lung injury. The Journal of clinical investigation. 2009;119(9]):2550-63. Epub 2009/08/05.
Ortiz-Stern A, Deng X, Smoktunowicz N, Mercer PF, Chambers RC. PAR-1-dependent and PAR-independent pro-inflammatory signaling in human lung fibroblasts exposed to thrombin. Journal of cellular physiology. 2012;227(11]):3575-84. Epub 2012/01/27.
Blanc-Brude OP, Archer F, Leoni P, Derian C, Bolsover S, Laurent GJ, et al. Factor Xa stimulates fibroblast procollagen production, proliferation, and calcium signaling via PAR1 activation. Exp Cell Res. 2005;304(1]):16-27. Epub 2005/02/15.
Pendurthi UR, Ngyuen M, Andrade-Gordon P, Petersen LC, Rao LV. Plasmin induces Cyr61 gene expression in fibroblasts via protease-activated receptor-1 and p44/42 mitogen-activated protein kinase-dependent signaling pathway. Arteriosclerosis, thrombosis, and vascular biology. 2002;22(9]):1421-6. Epub 2002/09/17.
Tran T, Stewart AG. Protease-activated receptor (PAR)-independent growth and pro-inflammatory actions of thrombin on human cultured airway smooth muscle. Br J Pharmacol. 2003;138(5]):865-75. Epub 2003/03/19.
Altrogge LM, Monard D. An assay for high-sensitivity detection of thrombin activity and determination of proteases activating or inactivating protease-activated receptors. Analytical biochemistry. 2000;277(1]):33-45. Epub 1999/12/28.
Majumdar M, Tarui T, Shi B, Akakura N, Ruf W, Takada Y. Plasmin-induced migration requires signaling through protease-activated receptor 1 and integrin alpha(9])beta(1]). The Journal of biological chemistry. 2004;279(36]):37528-34. Epub 2004/07/13.
Austin KM, Covic L, Kuliopulos A. Matrix metalloproteases and PAR1 activation. Blood. 2013;121(3]):431-9. Epub 2012/10/23.
Jono S, Shioi A, Ikari Y, Nishizawa Y. Vascular calcification in chronic kidney disease. Journal of bone and mineral metabolism. 2006;24(2]):176-81. Epub 2006/02/28.
Gunst SJ, Tang DD. The contractile apparatus and mechanical properties of airway smooth muscle. The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 2000;15(3]):600-16. Epub 2000/04/12.
Deng L, Bosse Y, Brown N, Chin LY, Connolly SC, Fairbank NJ, et al. Stress and strain in the contractile and cytoskeletal filaments of airway smooth muscle. Pulmonary pharmacology & therapeutics. 2009;22(5]):407-16. Epub 2009/05/05.
Smith PG, Roy C, Zhang YN, Chauduri S. Mechanical stress increases RhoA activation in airway smooth muscle cells. American journal of respiratory cell and molecular biology. 2003;28(4]):436-42. Epub 2003/03/26.
Hultgardh-Nilsson A, Durbeej M. Role of the extracellular matrix and its receptors in smooth muscle cell function: implications in vascular development and disease. Current opinion in lipidology. 2007;18(5]):540-5. Epub 2007/09/22.
Koyama H, Raines EW, Bornfeldt KE, Roberts JM, Ross R. Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation of Cdk2 inhibitors. Cell. 1996;87(6]):1069-78. Epub 1996/12/13.
Knight CG, Morton LF, Peachey AR, Tuckwell DS, Farndale RW, Barnes MJ. The collagen-binding A-domains of integrins alpha(1])beta(1]) and alpha(2])beta(1]) recognize the same specific amino acid sequence, GFOGER, in native (triple-helical) collagens. The Journal of biological chemistry. 2000;275(1]):35-40. Epub 2000/01/05.
Davis GE. Matricryptic sites control tissue injury responses in the cardiovascular system: relationships to pattern recognition receptor regulated events. Journal of molecular and cellular cardiology. 2010;48(3]):454-60. Epub 2009/09/16.
Nguyen TT, Ward JP, Hirst SJ. beta1-Integrins mediate enhancement of airway smooth muscle proliferation by collagen and fibronectin. American journal of respiratory and critical care medicine. 2005;171(3]):217-23. Epub 2004/10/27.
Freyer AM, Johnson SR, Hall IP. Effects of growth factors and extracellular matrix on survival of human airway smooth muscle cells. American journal of respiratory cell and molecular biology. 2001;25(5]):569-76. Epub 2001/11/20.
Millien VO, Lu W, Shaw J, Yuan X, Mak G, Roberts L, et al. Cleavage of fibrinogen by proteinases elicits allergic responses through Toll-like receptor 4. Science. 2013;341(6147]):792-6. Epub 2013/08/21.
Zhang W, Gunst SJ. Interactions of airway smooth muscle cells with their tissue matrix: implications for contraction. Proceedings of the American Thoracic Society. 2008;5(1]):32-9. Epub 2007/12/21.
Ghezzi CE, Risse PA, Marelli B, Muja N, Barralet JE, Martin JG, et al. An airway smooth muscle cell niche under physiological pulsatile flow culture using a tubular dense collagen construct. Biomaterials. 2013;34(8]):1954-66. Epub 2012/12/22.
Nho RS, Xia H, Kahm J, Kleidon J, Diebold D, Henke CA. Role of integrin-linked kinase in regulating phosphorylation of Akt and fibroblast survival in type I collagen matrices through a beta1 integrin viability signaling pathway. The Journal of biological chemistry. 2005;280(28]):26630-9. Epub 2005/05/21.
Xia H, Nho RS, Kahm J, Kleidon J, Henke CA. Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway. The Journal of biological chemistry. 2004;279(31]):33024-34. Epub 2004/05/29.
Balasubramanian L, Lo CM, Sham JS, Yip KP. Remanent cell traction force in renal vascular smooth muscle cells induced by integrin-mediated mechanotransduction. American journal of physiology Cell physiology. 2013;304(4]):C382-91. Epub 2013/01/18.
Hong Z, Sun Z, Li Z, Mesquitta WT, Trzeciakowski JP, Meininger GA. Coordination of fibronectin adhesion with contraction and relaxation in microvascular smooth muscle. Cardiovascular research. 2012;96(1]):73-80. Epub 2012/07/18.
Pelaia G, Renda T, Gallelli L, Vatrella A, Busceti MT, Agati S, et al. Molecular mechanisms underlying airway smooth muscle contraction and proliferation: Implications for asthma. Respiratory Medicine. 2008;102(8]):1173-81.
Adebayo O, Hookway TA, Hu JZ, Billiar KL, Rolle MW. Self-assembled smooth muscle cell tissue rings exhibit greater tensile strength than cell-seeded fibrin or collagen gel rings. Journal of biomedical materials research Part A. 2013;101(2]):428-37. Epub 2012/08/07.
Peyton SR, Raub CB, Keschrumrus VP, Putnam AJ. The use of poly(ethylene glycol) hydrogels to investigate the impact of ECM chemistry and mechanics on smooth muscle cells. Biomaterials. 2006;27(28]):4881-93. Epub 2006/06/10.
Marinkovic A, Liu F, Tschumperlin DJ. Matrices of physiologic stiffness potently inactivate idiopathic pulmonary fibrosis fibroblasts. American journal of respiratory cell and molecular biology. 2013;48(4]):422-30. Epub 2012/12/22.
Sazonova OV, Isenberg BC, Herrmann J, Lee KL, Purwada A, Valentine AD, et al. Extracellular matrix presentation modulates vascular smooth muscle cell mechanotransduction. Matrix biology : journal of the International Society for Matrix Biology. 2014. Epub 2014/12/03.
Sun Z, Martinez-Lemus LA, Hill MA, Meininger GA. Extracellular matrix-specific focal adhesions in vascular smooth muscle produce mechanically active adhesion sites. American journal of physiology Cell physiology. 2008;295(1]):C268-78. Epub 2008/05/23.
Smith HW, Marshall CJ. Regulation of cell signalling by uPAR. Nature reviews Molecular cell biology. 2010;11(1]):23-36. Epub 2009/12/23.
Billington CK, Ojo OO, Penn RB, Ito S. cAMP regulation of airway smooth muscle function. Pulmonary pharmacology & therapeutics. 2013;26(1]):112-20. Epub 2012/05/29.
Simonneau G, Torbicki A, Hoeper MM, Delcroix M, Karlocai K, Galie N, et al. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. The European respiratory journal. 2012;40(4]):874-80. Epub 2012/03/01.
Li RC, Cindrova-Davies T, Skepper JN, Sellers LA. Prostacyclin induces apoptosis of vascular smooth muscle cells by a cAMP-mediated inhibition of extracellular signal-regulated kinase activity and can counteract the mitogenic activity of endothelin-1 or basic fibroblast growth factor. Circulation research. 2004;94(6]):759-67. Epub 2004/02/14.
Deshpande SR, Satyanarayana K, Rao MN, Pai KV. Nitric oxide modulators: an emerging class of medicinal agents. Indian journal of pharmaceutical sciences. 2012;74(6]):487-97. Epub 2013/06/27.
Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, et al. Reversal of experimental pulmonary hypertension by PDGF inhibition. The Journal of clinical investigation. 2005;115(10]):2811-21. Epub 2005/10/04.
Mucke H. The role of imatinib in the treatment of pulmonary hypertension. Drugs Today (Barc). 2013;49(3]):203-11. Epub 2013/03/26.
Yndestad A, Larsen KO, Oie E, Ueland T, Smith C, Halvorsen B, et al. Elevated levels of activin A in clinical and experimental pulmonary hypertension. J Appl Physiol (1985]). 2009;106(4]):1356-64. Epub 2009/02/07.
Makinde T, Murphy RF, Agrawal DK. The regulatory role of TGF-beta in airway remodeling in asthma. Immunol Cell Biol. 2007;85(5]):348-56. Epub 2007/02/28.
Kitamura H, Cambier S, Somanath S, Barker T, Minagawa S, Markovics J, et al. Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin alphavbeta8-mediated activation of TGF-beta. The Journal of clinical investigation. 2011;121(7]):2863-75. Epub 2011/06/08.
Xie S, Sukkar MB, Issa R, Oltmanns U, Nicholson AG, Chung KF. Regulation of TGF-beta 1-induced connective tissue growth factor expression in airway smooth muscle cells. American journal of physiology Lung cellular and molecular physiology. 2005;288(1]):L68-76. Epub 2004/09/21.
Wynn TA. Integrating mechanisms of pulmonary fibrosis. J Exp Med. 2011;208(7]):1339-50. Epub 2011/07/06.
de Kretser DM, O'Hehir RE, Hardy CL, Hedger MP. The roles of activin A and its binding protein, follistatin, in inflammation and tissue repair. Molecular and cellular endocrinology. 2012;359(1-2]):101-6. Epub 2011/11/01.
Lee KS, Jin SM, Kim SS, Lee YC. Doxycycline reduces airway inflammation and hyperresponsiveness in a murine model of toluene diisocyanate-induced asthma. The Journal of allergy and clinical immunology. 2004;113(5]):902-9. Epub 2004/05/08.
Neto-Neves EM, Sousa-Santos O, Ferraz KC, Rizzi E, Ceron CS, Romano MM, et al. Matrix metalloproteinase inhibition attenuates right ventricular dysfunction and improves responses to dobutamine during acute pulmonary thromboembolism. Journal of cellular and molecular medicine. 2013;17(12]):1588-97. Epub 2013/11/10.
Shinagawa K, Martin JA, Ploplis VA, Castellino FJ. Coagulation factor Xa modulates airway remodeling in a murine model of asthma. American journal of respiratory and critical care medicine. 2007;175(2]):136-43. Epub 2006/11/04.
Swaisgood CM, French EL, Noga C, Simon RH, Ploplis VA. The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system. The American journal of pathology. 2000;157(1]):177-87. Epub 2000/07/06.
Suzuki J, Ogawa M, Muto S, Yamaguchi Y, Itai A, Isobe M. The effects of pharmacological PAI-1 inhibition on thrombus formation and neointima formation after arterial injury. Expert Opin Ther Targets. 2008;12(7]):783-94. Epub 2008/06/17.
Eitzman DT, McCoy RD, Zheng X, Fay WP, Shen T, Ginsburg D, et al. Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. The Journal of clinical investigation. 1996;97(1]):232-7. Epub 1996/01/01.
Lee SH, Eren M, Vaughan DE, Schleimer RP, Cho SH. A plasminogen activator inhibitor-1 inhibitor reduces airway remodeling in a murine model of chronic asthma. American journal of respiratory cell and molecular biology. 2012;46(6]):842-6. Epub 2012/02/11.
Arndt PG, Young SK, Worthen GS. Regulation of lipopolysaccharide-induced lung inflammation by plasminogen activator Inhibitor-1 through a JNK-mediated pathway. J Immunology. 2005;175(6]):4049-59.
Savov JD, Brass DM, Berman KG, McElvania E, Schwartz DA. Fibrinolysis in LPS-induced chronic airway disease. American journal of physiology Lung cellular and molecular physiology. 2003;285(4]):L940-8.
Ploplis VA, Castellino FJ. Attenuation of neointima formation following arterial injury in PAI-1 deficient mice. Ann N Y Acad Sci. 2001;936:466-8. Epub 2001/07/20.
Kogushi M, Matsuoka T, Kuramochi H, Murakami K, Kawata T, Kimura A, et al. Oral administration of the thrombin receptor antagonist E5555 (atopaxar) attenuates intimal thickening following balloon injury in rats. European journal of pharmacology. 2011;666(1-3]):158-64. Epub 2011/06/04.
Chieng-Yane P, Bocquet A, Letienne R, Bourbon T, Sablayrolles S, Perez M, et al. Protease-activated receptor-1 antagonist F 16618 reduces arterial restenosis by down-regulation of tumor necrosis factor alpha and matrix metalloproteinase 7 expression, migration, and proliferation of vascular smooth muscle cells. The Journal of pharmacology and experimental therapeutics. 2011;336(3]):643-51. Epub 2010/12/09.
Wang XQ, Bdeir K, Yarovoi SV, Cines DB, Fang W, Abraham E. Involvement of the urokinase kringle domain in lipopolysaccharide-induced acute lung injury. Journal of Immunology. 2006;177(8]):5550-7.
Abraham E, Gyetko MR, Kuhn K, Arcaroli J, Strassheim D, Park JS, et al. Urokinase-type plasminogen activator potentiates lipopolysaccharide-induced neutrophil activation. J Immunol. 2003;170(11]):5644-51. Epub 2003/05/22.
de Boer JD, Majoor CJ, van 't Veer C, Bel EH, van der Poll T. Asthma and coagulation. Blood. 2012;119(14]):3236-44. Epub 2012/01/21.
Graff J, Harder S. Anticoagulant therapy with the oral direct factor Xa inhibitors rivaroxaban, apixaban and edoxaban and the thrombin inhibitor dabigatran etexilate in patients with hepatic impairment. Clin Pharmacokinet. 2013;52(4]):243-54. Epub 2013/02/08.
French SL, Arthur JF, Tran HA, Hamilton JR. Approval of the first protease-activated receptor antagonist: Rationale, development, significance, and considerations of a novel anti-platelet agent. Blood reviews. 2014. Epub 2014/12/04.
Capodanno D, Bhatt DL, Goto S, O'Donoghue ML, Moliterno DJ, Tamburino C, et al. Safety and efficacy of protease-activated receptor-1 antagonists in patients with coronary artery disease: a meta-analysis of randomized clinical trials. Journal of thrombosis and haemostasis : JTH. 2012;10(10]):2006-15. Epub 2012/08/01.
Tuinman PR, Dixon B, Levi M, Juffermans NP, Schultz MJ. Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations. Crit Care. 2012;16(2]):R70. Epub 2012/05/02.
Lippi G, Mattiuzzi C, Favaloro EJ. Novel and Emerging Therapies: Thrombus-Targeted Fibrinolysis. Seminars in thrombosis and hemostasis. 2012. Epub 2012/10/05.
Schuliga M, Westall G, Xia Y, Stewart AG. The plasminogen activation system: new targets in lung inflammation and remodeling. Curr Opin Pharmacol. 2013;13(3]):386-93. Epub 2013/06/06.
Goldsmith AM, Bentley JK, Zhou L, Jia Y, Bitar KN, Fingar DC, et al. Transforming growth factor-beta induces airway smooth muscle hypertrophy. American journal of respiratory cell and molecular biology. 2006;34(2]):247-54. Epub 2005/10/22.
Gunst SJ, Tang DD. The contractile apparatus and mechanical properties of airway smooth muscle. Eur Respir J. 2000;15(3]):600-16. Epub 2000/04/12.
Smith PG, Deng L, Fredberg JJ, Maksym GN. Mechanical strain increases cell stiffness through cytoskeletal filament reorganization. Am J Physiol Lung Cell Mol Physiol. 2003;285(2]):L456-63. Epub 2003/04/22.
Stehn JR, Schevzov G, O'Neill GM, Gunning PW. Specialisation of the tropomyosin composition of actin filaments provides new potential targets for chemotherapy. Curr Cancer Drug Targets. 2006;6(3]):245-56. Epub 2006/05/23.
Lin AH, Eliceiri BP, Levin EG. FAK mediates the inhibition of glioma cell migration by truncated 24 kDa FGF-2. Biochem Biophys Res Commun. 2009;382(3]):503-7. Epub 2009/03/24.
Sawhney RS, Cookson MM, Omar Y, Hauser J, Brattain MG. Integrin alpha2-mediated ERK and calpain activation play a critical role in cell adhesion and motility via focal adhesion kinase signaling: identification of a novel signaling pathway. J Biol Chem. 2006;281(13]):8497-510. Epub 2006/02/08.
Chan MW, Arora PD, Bozavikov P, McCulloch CA. FAK, PIP5KIgamma and gelsolin cooperatively mediate force-induced expression of alpha-smooth muscle actin. J Cell Sci. 2009;122(Pt 15]):2769-81. Epub 2009/07/15.