An overview of the role of MMP-8 and ADAM-33 in bronchial asthma

Abstract

Matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs) are enzymes able to degrade a variety of protein components of the extracellular matrix. Due to the diverse role of MMPs and ADAMs, they are involved in the pathogenesis of many diseases, including chronic inflammatory lung diseases. In this review, the objective is to summarize the current knowledge about the role of the two enzymes from the respective families, namely MMP-8 and ADAM-33, in Bronchial asthma in order to explore the possibility for their expression, polymorphisms or serum/BAL (Bronchoalveolar Lavage) concentration to be used as biomarkers or targets for future target therapy. Considering the key functions of MMP-8 and ADAM-33 in many pathologic conditions, development of proper inhibitors of their action might be useful tools in the treatment approaches. However, a lot of knowledge has yet to be gained about these enzymes and their role in bronchial asthma, since some of the mechanisms are unknown or not discovered yet.

Keywords:

• MMP-8
• ADAM-33
• lung
• inflammation
• bronchial asthma

Introduction

Matrix metalloproteinases (MMP) are enzymes belonging to the group of zinc-dependent endopeptidases that can degrade virtually all protein components of the extracellular matrix (ECM). MMPs are involved in a variety of physiological processes such as morphogenesis, angiogenesis, tissue remodeling, repair mechanisms and apoptosis. According to their functions, characteristics and properties, they are classified into eight groups [1].

A disintegrin and metalloproteinase (ADAM) belongs to a family of cell-surface metalloproteinases, having both adhesive and proteolytic activities. They are implicated in shedding of membrane-bound proteins as growth factors, cytokines, receptors and adhesion molecules [2].

Besides their role in a variety of physiological processes, MMPs and ADAMs are involved in practically all types of pathological conditions, especially those associated with acute or chronic inflammation [3–10]. In this context, the tight regulation of their expression, activation and enzyme activity has the key role of maintaining tissue homeostasis.

The aim of this review paper is to summarize the current knowledge about MMP-8 and ADAM-33 in bronchial asthma in order to explore the possibility for their expression, polymorphisms or serum/BAL (Bronchoalveolar Lavage) concentration to have an application as biomarkers or targets for future target therapy.

Matrix metalloproteinases

MMP structure and function

Structure

MMPs are multidomain enzymes, which belong to the metzincin super-family of proteases, having a motif in the catalytic domain with three histidine residues, which binds the zinc ion. There are four common domains in the structure of the typical MMPs: pro-peptide, catalytic domain, ‘hinge region’ (a linker peptide) and a hemopexin domain (Figure 1) [11–19].

Figure 1. The basic structure of MMPs and ADAMs. (A) The four common domains in MMPs: pro-peptide domain, catalytic metalloproteinase domain, hinge region and hemopexin domain. (B) Unlike MMPs, ADAMs contain a disintegrin domain, cysteine-rich domain, EGF-like domain, transmembrane region and a cytoplasmic tail (transmembrane anchor) (adapted from Edwards et al. [11,12]).

The pro-peptide domain, with about 80 amino acids, has an important regulatory function. MMPs are synthesized as zymogens (inactive enzyme with the pro-peptide) and are activated via the proteolysis of the zymogen (zymogen activation). A cysteine residue of the pro-peptide involved in the ‘cysteine switch’ mechanism binds to the zinc ion (Zn²⁺) in the active site of the metalloproteinase domain and thus prevents the substrate binding [17–19]. The ‘hinge region’ contains about 75 amino acids and provides a flexible connection between the metalloproteinase catalytic domain and hemopexin domain. The hemopexin (Hpx) domain with about 200 amino acids is important for the protein–protein interaction and contributes to the substrate specificity and binding to TIMPs (tissue inhibitors of metalloproteinases) [17–19]. Besides this typical structural organization, there are some variations in some MMPs: MMP-7, MMP-23 and MMP-26 lack the ‘hinge region’ and the Hpx domain; MMP-23 has an additional cysteine-rich and Ig-like (CysR-Ig) domain; gelatinases (MMP-2 and MMP-9) have three finbronectin type II-like (FN2) motifs in the catalytic domain; Membrane-type MMPs (MT1-, MT2-, MT3- and MT5-MMPs) have transmembrane (TM) and cytoplasmic (Cyt) domains; and the membrane-type MT4- and MT6-MMPs contain the glycosylphosphatidylinositol (GPI) anchoring sequence; several MMPs also contain the furin recognition sequence in the pro-pepride [20].

According to their functions, structural characteristics and properties, MMPs can be classified into collagenases (MMP-1, MMP-8, MMP-13 and MMP-18), gelatinases (MMP-2 and MMP-9), matrilysins (MMP-7, MMP-26 and MMP-11), stromelysins (MMP-3 and MMP-10), transmembrane type (MT1-, MT2-, MT3- and MT5-MMPs), GPI-anchored (MT4- and MT6-MMPs) and other MMPs (MMP-12, −19, −20, −21, −23, −27 and −28) [15,20–23].

Function

The main substrates of collagenases are the triple-helical fibrillar collagens type I, II and III, as well as other proteins in ECM and soluble proteins [20]. Gelatinases can degrade network-forming collagens type IV, V and XI, gelatin, the other basement membrane protein, laminin, and the core protein of the proteoglycans. Although the stromelysins show the same structural organization as collagenases, they are unable to degrade the fibrillar collagens, but they can cleave a variety of ECM proteins and are involved in proMMP activation [20]. Matrilysins, especially MMP-7, cleave not only the ECM proteins, but also process cell surface proteins, such as Fas ligand, pro-TNF-α, pro-α-defensin, E-cadherin [20]. The membrane-type MMPs, which are activated by the intracellular protease furin, can activate proMMP-2 and one of them (MT1-MMP) can cleave the fibrillar collagens type I, II and III [18–20].

The degradation and remodeling of ECM proteins carried out by MMPs and other extracellular proteases allows many molecular processes, such as cell proliferation, migration, differentiation, tissue repair, angiogenesis and immune response [3–5,17,20]. In addition, the proteolytic cleavage of growth factors and membrane receptors are/is crucial for cell signaling. By cleavage of growth factors on the cell surface or a controlled cleavage of growth factor-binding proteins, the signal becomes available for cells which are not in the direct environment or on the contrary; it leads to termination of signaling or migration [24]. Hereby, any alteration in MMP activity would lead to either deposition or loss of ECM proteins and altered regulation of cell processes, which can consequently result in different pathological manifestations [17,25,26].

MMP activation and regulation

The catalytic characteristics of MMPs as proteases require their secretion as inactive pro-enzymes. Since MMPs possess a variety of functions, they can be activated by many factors as well as regulated at different levels. MMPs are synthesized as pre-pro-enzymes, which are transformed during posttranslational modification by removing the signal peptide to pro-enzyme, known as zymogen. The zymogen activation is the final step to fully activate the MMP by cleavage of the pro-peptide. Enzymes which can cleave the pro-peptide and remove the inhibitory cysteine switch from the active site, are serine proteases such as the intracellular furin, plasmin and other MMPs [13,15,27].

The activity of MMPs could be influenced by several physicochemical agents like heat, low pH, thiol modifying agents, oxidized glutathione [9,17,28]. However, the pivotal specific endogenous regulators of MMPs are the Tissue inhibitors of matrix metalloproteinases (TIMPs) (Table 1) [1,29–42]. The human body has four types of TIMPs, which have different inhibition specificity to MMPs. In general, each TIMP has two domains: a larger N-terminal domain and a smaller C-terminal domain [15]. The inhibitory effect of TIMPs is carried out by the N-terminal domain which binds to the catalytic domain of MMPs and in this way prevents the substrate interactions. The ability of the N-terminal domain to bind the active catalytic domain of a MMP is due to the similarity of the N-terminal domain with the substrate sequence P1-P1´-P2´-P3´ [11].

Table 1. Tissue inhibitors of metalloproteinases (TIMPs): expression and interactions (adapted from Cabral-Pacheco et al. [1]).

TIMPs	Tissue/cell expression	Localization	MMPs and ADAM inhibited	Other interactions	References
TIMP-1	Transcription inducible by cytokines and hormones: lymph nodes, brain, heart, arteries, colon, kidneys, liver, lungs, bladder, breasts, skin, ovaries, uterus, prostate, and testes	Soluble within the interstitial space of the ECM, and cell surface.	MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-19, MT1-MMP, MT3-MMP, MT5-MMP, ADAM-10	pro-MMP-9, LRP1, CD 63	[29–32]
TIMP-2	Constitutive expression: lymph nodes, brain, heart, arteries, colon, kidneys, liver, breasts, ovaries, prostate, and testes	Soluble within the interstitial space of the ECM, and cell surface.	MMP-2, MMP-9, MT1- MMP, ADAM-12	pro-MMP-2, α3β1 integrin, LRP1	[31–34]
TIMP-3	In response to mitogenic stimulation and during cell cycle progression: brain, heart, colon, kidneys, lungs, liver, breast, ovaries, prostate and testes, and eyes	Extracellular matrix and cell surface via heparan sulphate proteoglycans.	MMP-2, MMP-9, ADAM-17, ADAM-10	pro-MMP-2, pro-MMP-9	[35–38]
TIMP-4	heart, brain, breasts, uterus, ovary, kidney, pancreas, colon, testes, adipose tissue and prostate	Soluble within the interstitial space of the ECM, and cell surface.	MMP-2, MMP-26, MT1-MMP, ADAM-28	pro-MMP-2, CD 63	[20,39]
LRP1- Low density lipoprotein receptor-related protein 1

TIMP-1 is secreted by the majority of cell types but its amount is more restricted compared to the other three types since it highly inhibits MMP-9. TIMP-2 is also secreted by the majority of cell types but it is not induced by growth factors. TIMP-3 is released into the ECM and in the basal layer of the eyes and kidneys. TIMP-4 is secreted in the heart, ovaries, kidneys, pancreas, colon, testes, brain and adipose tissue [1,20,43].

In addition to the MMP inhibitory effect, some TIMPs are also important pro-MMP activators [17]. While the N-terminal domains are involved in binding and inhibiting the catalytic domain, the C-terminal domains of TIMPs are involved in protein-protein interaction, which is essential in some zymogen activation: the C-terminal domain binds to the hemopexin domain of the MMP and thus initiates the zymogen activation. For example, TIMP-2 builds a complex with proMMP-2 by binding the TIMP-2 C-terminal domain with the pro-MMP-2 hemopexin domain. The complex then interacts with another MMP molecule on the cell surface, MT1-MMP, and the pro-MMP-2/TIMP-2/MT1-MMP complex leads to activation of MMP-2 [1,11,28].

In addition to TIMPs, the inhibition of active MMPs is also performed by α2-macroglobulin. α2-Macroglobulin performs the inhibition by binding to the catalytic domain and thus preventing further substrate interaction [1,15,28].

If imbalance occurs in the equilibrium of MMPs (proteolytic function) and inhibitory proteins (TIMPs or other protease inhibitors), development of a disease might result. The extensive proteolytic activity would lead to diseases like emphysema or rheumatoid arthritis, while the prevalence of MMPs inhibitors would result in intensive ECM deposition and further in fibrosis [7,44–50].

A disintegrin and metalloproteinase (ADAM)

ADAM structure and function

Structure

Like MMPs, ADAMs are multidomain enzymes which also belong to the metzincin superfamily. Since ADAMs have proteolytic effects like MMPs, there is quite high similarity in the structural organization of both protease families: like MMPs, ADAMs possess a pro-peptide domain and zinc-binding metalloproteinase catalytic domain. In addition, they also contain a disintegrin, cysteine-rich and EGF-like domains, a transmembrane region and a cytoplasmic tail (Figure 1) [51].

Since ADAMs are proteolytic enzymes, the metalloproteinase catalytic domain has a key role in the activity. Similar to the MMPs, the catalytic domain of ADAMs contains a Zinc ion (Zn²⁺) and a sequence with three histidine residues for its stabilization. A number of ADAMs, including ADAM-33, but not ADAM-17, possess Ca²⁺ in the catalytic domain, which has a role in stabilization of the metalloproteinase domain [11,52,53].

The metalloproteinase catalytic domain of ADAMs is connected to the disintegrin domain with a short ‘hinge region’, which provides a small degree of flexibility. The disintegrin domain is responsible for the interaction of ADAM with the heterodimeric adhesion proteins, integrins [2,11,53].

ADAMs are characterized by a transmembrane region and a cytoplasmic tail, although it is not clear what function this cytoplasmic domain has. However, it is believed that it has a role in cell signaling since the cytoplasmic tail contains tyrosine residues that could be targets for phosphorylation by some tyrosine kinases and thus, they could be binding sites for downstream SH2-domain containing signaling molecules [11].

Function

One of the main functions of ADAMs is the ectodomain shedding which is essential for most of the important signaling pathways. It is known that EGF (epidermal growth factor), HB-EGF (heparin-binding EGF), TGF-α (transforming growth factor α), epiregulin, amphiregulin and betacellulin are produced as membrane-associated molecules. ADAMs catalyze the proteolytic cleavage and shedding of the biologically active ligand from the membrane surface. This ectodomain shedding and activation could be used for several signal transduction pathways via paracrine, autocrine and juxtacrine mechanisms of action [54,55].

Besides the ectodomain shedding, there are also some other processes in the human body in which ADAMs are involved. These are sperm-egg interactions, cell fate determination in the nervous system, cell migration, axon guidance, muscle development and diverse aspects of immunity [11]. Since ADAMs, like MMPs, have proteolytic activities, they are involved in many diseases like tumor growth and metastasis and bronchial asthma [56–59].

ADAM activation and regulation

The similarities of ADAMs to MMPs could also be found in the activation and regulation. Due to the metalloproteinase catalytic domain, a self-protection mechanism against cell self-degradation is needed. Similarly to MMPs, the pro-peptide domain performs this important function via the ‘cysteine switch’ mechanism. Most ADAMs are activated intracellularly by pro-peptide domain removal carried out by pro-protein convertases, such as furin, during the enzyme secretion pathway [52]. After the cleavage, the pro-peptide domain has different functions in the ADAM regulation. On the one hand, it can act as a selective inhibitor of the activated ADAM, but it also possesses the ability of a chaperon and to protect the active enzyme from degradation [11,60].

Like MMPs, the pivotal endogenous inhibitors of ADAMs are the TIMPs, as some TIMPs are naturally more specific to ADAMs than to MMPs. TIMP-3 particularly, shows a broad spectrum of specificity to almost all ADAMs [61]. However, some ADAMS, such as ADAM-8, −9 and −19, have been shown to be insen­sitive to the inhibitory effect of TIMPs. As earlier discussed, the main mechanism of inhibition is the binding of the N-terminal domain of TIMP to the active site of the activated enzyme (MMP or ADAM), which leads to prevention of substrate interactions [11,53]. This explains why the sequence of the N-terminal domain of TIMPs is crucial for the proper function of TIMPs. Altered sequences can lead to TIMP dysfunction. Besides the N-terminal domain of TIMPs, it has been found that the full-length forms of TIMPs also take part in the regulation of the ADAM enzymes. The N-terminal domain of TIMP-1 and −2 as selective inhibitors of ADAM-10 are ineffective, whereas the full-length TIMPs work properly [11,53,55].

Association of MMP-8 and ADAM-33 with bronchial asthma

Airway remodeling in bronchial asthma

Asthma is a chronic lung disease which leads to bronchoconstriction and thickening of the lung airways usually by an allergic inflammation process. It has been found that in different phenotypes in asthma different immune cells such as lymphocytes, mast cells, eosinophils and neutrophils might play a role in the inflammation process [62]. Mainly by remodeling the ECM, this inflammation process leads to a loss of lung function. Asthma cannot be cured but can be controlled [63,64]. In this respect studying the exact pathogenesis of asthma and the risk factors can be helpful in inventing novel therapeutic approaches.

ECM is an important component of the connective tissue: it defines the structure of cells, provides stability in the lung and the overall lung function. The main components of ECM are collagen and elastic fibers, proteoglycans and glycoproteins. Collagen fibers are essential for the mechanical characteristics of the lung. Type I and III collagens are found in the alveolar wall and alveolar septa contributing to lung mechanics, while type IV is found in the basement membrane zone [65]. Hereby, the ratio of type I and III collagen is crucial for the mechanical characteristics of the lungs and the stability of the fibers, since collagen type I is stiffer than type III. Elastic fibers are important for the elastic property of the lungs, especially for the proper recoil of the lungs. Deficiency or loss of elastic fibers can lead to emphysema which is characterized by air trapping in the smallest alveoli due to loss of recoil [66].

In Bronchial asthma, usually an inhaled allergen triggers an immune response. Once the allergen gets in contact with the mucosa which lines the bronchial epithelium, it will be captured by antigen-presenting cells and presented to T helper lymphocytes which trigger the release of Th2 cells and pro-inflammatory cytokines and chemokines. Since this immune activation by an allergen could be repeated, the immune response in bronchial asthma leads to a chronic inflammation of the airways. Eventually the permanent inflammation increases the epithelial stress of the lung tissue and leads to airway remodeling with structural changes of the organ. The typical structural changes during the chronic inflammation in bronchial asthma are subepithelial reticular basement membrane thickening, increased airway smooth muscle thickness, angiogenesis and goblet cell hyperplasia associated with irreversible loss of lung function [66]. Pohunek et al. [67] have reported thickness of the subepithelial lamina reticularis in the lung tissue biopsy of children (age: 1.2 to 11.7) with chronic respiratory symptoms, indicating that epithelial tissue remodeling can be already performed before the onset of the first symptoms of bronchial asthma. Another important factor in the pathophysiology of bronchial asthma is the airway smooth muscle hyperplasia and hypertrophy related to more severe bronchial asthma. According to Slats et al. [68], the expression of α-smooth muscle actin, desmin and elastin leads to airway thickening. Besides that, TGF-β, which is a pleiotropic cytokine controlling both pro- and anti-inflammatory responses, is an airway remodeling factor as well, since it activates the fibroblast to produce and deposit collagen type I and II, fibronectin and proteoglycans.

One of the possible treatments for bronchial asthma patients are inhaled corticosteroids. The latter inhibit the inflammation process, supress the MMP activity and improve the symptoms [66–69].

MMP-8 in bronchial asthma

The pathogenesis of bronchial asthma is related to a change in the quantity and ratio of ECM components in lungs, which leads to airway remodeling and to the typical bronchial asthma pathologies. Because MMPs are some of the major enzymes involved in ECM remodeling, it has been found that they play a significant role in the pathogenesis of the disease [70].

MMP-8 is classified as collagenase-2, degrading collagen. In the lung tissue the main substrates of MMP-8 are collagens type I, III, VII and X. Furthermore, it inactivates the serine proteinase inhibitors α1-antitrypsin and α1-antichymotrypsin, and even the broad-spectrum proteinase inhibitor α2-macroglobulin [71]. By cleavage of collagens and degradation of the proteinase inhibitors and chemokines, MMP-8 may play a role in inflammation influencing the inflammatory cell trafficking.

It has been found that MMP-8 can be secreted by polymorphonuclear leukocytes (PMNs or neutrophils). Besides that, non-PMN cells like human bronchial epithelial cells, sulcular epithelial cell, chondrocytes, synovial fibroblasts, endothelial cells, odontoblast and plasma cells secrete the major quantity of MMP-8 [72]. Studies have shown that high MMP-8 levels are directly linked to the pathogenesis of bronchial asthma. Increased levels of various MMPs, including MMP-8, have been reported in induced sputum from asthmatics [73]. Even more, a significant difference in the levels of MMP-8, as well as of FGF-2, MMP-1, MMP-12 and TIMP-1 has been reported between control groups, patients with mild to moderate asthma and patients with severe asthma [73]. In a larger study, including 121 patients with severe asthma and 8 controls, the authors have described significantly higher level of MMP-8 in induced sputum in asthmatic patients than in controls. Other biomarkers with higher levels in the sputum of the patients in comparison with controls are also MMP-1, MMP-3, MMP-12, VEGF, IL-6, soluble IL-6R, IL-5, IL-8, YKL-40, while TIMP-1, IL-2, IL-1RA and FGF have been reported with decreased levels [74]. An excess of MMP-8 secretion has been also reported in BALF of patients with bronchiectasis and has correlated with disease severity [75]. In atopic COPD patients (having also higher IgE) the serum level of MMP-8 has been shown to be significantly higher than in non-atopic COPD and to correlate positively with the rate of leukocytes and neutrophils and with presence of more severe symptoms [76].

In steroid naive and untreated asthma patients, high levels of MMP-8 in the BALF have been found. At the same time, there has been no evidence of increased MMP-8 levels in intact and repaired asthmatic epithelium. These results suggest that due to initial inflammation processes in bronchial asthma, PMN cells as well as non-PMN cells produce and secret MMP-8 which increases the risk of subepithelial collagenolysis and deposition of collagen type I, III, V and fibronectin which leads to thickening of subepithelial lamina reticularis [67].

A study designed by Gueders et al. [71] found that in C57BL/6 asthma model mice exposed to allergens, MMP-8−/− mice developed airway inflammation, accompanied by enhanced levels of IL-4, specific antiallergen IgE, in BALF and IgG1 in serum, as well as by reduced inflammatory cell apoptosis. The authors have suggested that MMP-8 may have an anti-inflammatory effect possibly by regulation of inflammatory cell apoptosis [71].

In clinical settings, physicians use spirometry for defining the severity and for characterization of bronchial asthma. In a study by Prick et al. [72], an inverse correlation was found between MMP-8 levels in BALF and FEV1 (forced expiratory volume in one second) and activation of MMP-8 only in BALF from steroid-naive and uncontrolled severe asthma patients. The results have shed light on the role of MMP-8 in worsening the lung function, airway destruction, healing, remodeling and treatment response in asthma [72].

These results suggest that MMP-8 might be used in the treatment evaluation of asthma patients concerning the severity and possible treatment failure. In the use of MMP-8 as an indicator for possible corticosteroid treatment failure, Elliot et al. [77] have reported that in post-mortem airway biopsies from asthmatic patients, some structural changes that lead to hyper­responsiveness might be partly independent of in­flammation and, therefore, are not reversible by anti-inflammatory treatment [77]. Asthmatics with neutrophilic inflammation show poor responses to corticosteroid therapy unlike those with eosinophilic inflammation, that is why a personalized treatment has been generally recognized as the most effective in asthmatics [78].

Besides exogenous factors, endogenous ones (such as single nucleotide polymorphisms, SNPs) might play a role in the development of bronchial asthma. It has been found that genes encoding MMPs are highly polymorphic. Data have shown that some polymorphisms in the MMP8 gene together with high serum concentrations are associated with the early development and more severe course of a number of lung diseases, including bronchial asthma [72,79,80].

According to Shimoda et al. [79], asthmatic patients with minor A allele of the MMP8 − 815 C > A (rs17099451 or −815 G > T) SNP might have a suppressive effect on asthma development. The major C allele, possibly by changing the promoter activity and gene expression, may lead to losing the suppression of inflammation, resulting in an increase in airway inflammation and remodeling and the development of asthma [79].

Another SNP, the transition from G to A in the promoter region of MMP8 (rs11225395, −799 G > A or C > T) has been shown to alter the promoter activity with minor A (T) allele resulting in significantly higher mRNA and protein expression than the major G (C) allele [81]. This polymorphism has been associated with a variety of pathological conditions such as breast cancer [82], colorectal cancer [83], sepsis [81], arterial hypertension [84]. No reports regarding this SNP and bronchial asthma have been found in the scientific literature. In this respect, it would be interesting to elucidate the role of this polymorphism on the serum levels of the enzyme in asthmatics and on the risk of bronchial asthma.

ADAM-33 in bronchial asthma

As ADAMs are some of the enzymes degrading ECM compounds, they are involved in cell signaling and tissue remodeling. They have the ability to modify cell surface receptor expression, release growth factors and soluble ectodomains and impact cell proliferation, differentiation, signaling and apoptosis [85]. ADAM-33 has been identified as a key protease in airway hyper-responsiveness and airway wall remodeling. It has been found that ADAM-33 has the ability to promote vessel formation and by that it may contribute to inflammation in the lungs and provide a source of nutrients for the developing smooth muscle [86]. On the other hand, ADAM-33 is involved in smooth muscle development supported by the fact that the enzyme is present in embryonic mesenchymal cells and in adult bronchial smooth muscle [87]. An increase in the number of fibroblast and smooth muscle cells has been found in soluble ADAM-33-induced airway remodeling [85].

The gene of ADAM-33 is highly polymorphic with 14119 base pairs, 22 exons and 21 introns [88]. It is located on chromosome 20p13. It has been found that 135 SNPs in ADAM33 are in connection with Bronchial asthma, and 14 of them have been indicated as possibly associated with asthma in different ethnic populations in the United States, Holland and Germany [89]. The SNPs affect mainly the transmembrane and cytoplasmic domain as well as the 3’UTR (3′ untranslated region) of ADAM-33. The importance of the transmembrane and cytoplasmic domains is explained with the abundance of proline residues in these regions which are involved in signaling by binding with downstream signaling proteins [89].

SNPs in ADAM33 have been associated with impaired lung function in young children and a faster decline in lung function in asthmatics and healthy individuals as well [90,91]. Several of the ADAM33 polymorphisms have been associated with more rapid decline in lung function in the general population [92] and in the asthma population [93]. The rs2280091 (A > G) SNP has been associated with an increased risk for asthma in Taiwanese [94], Saudi children [95] and Pakistani population [96]. Interestingly, in the Taiwanese population, the A allele has been associated with higher eosinophil count and increased hyperresponsiveness compared to the C allele [94], whereas in the Pakistani it has been the opposite [96]. This might be explained by the fact that aside from the SNPs themselves, the environmental and lifestyle factors have an impact on the gene expression. In this respect, the population differences should not be underestimated either. In addition, the risk of asthma may be higher in the presence of other genetic variations, suggesting an additive effect [94]. Together with rs2280091, in aeroallergen-induced asthma in the population of West Bengal, India, a significant association of rs2280090 T1 (A > G) polymorphisms in ADAM33 with asthma has been established [97].

Another polymorphism in ADAM33, rs2787094 (G > C), has also been associated with asthma. The CC genotype of this SNP has been related to asthma, increased sensitivity to allergens such as weeds, deteriorated lung function (FVC and FEV1), poor treatment responsiveness to ICS + LAB [98–100] and high risk of childhood asthma [101]. In a meta-analysis this polymorphism has been found as a risk factor for asthma with no significant differences in population selectivity [102]. In a previous meta-analysis, the rs2787094 polymorphism in the ADAM33 gene has been identified as a risk factor for asthma, especially in the Asian population [103]. In contrast, some authors reported no association of SNP and asthma [104,105].

Reports have shown ADAM33 rs528557/S2 (G > C) SNP to be associated with asthma susceptibility in Thai [106,107], European [108] and other populations [109], suggesting the opportunity to use the SNP as an early biomarker for asthma. Tripathi et al. [110] reported that ADAM-33 in bronchial asthma is expressed in the airway smooth muscle cells, mesenchymal cells and airway epithelium [110]. Higher expression of ADAM-33 in the lung tissue, analogously to MMP-8, has been associated with a declined FEV1 [72]. ADAM-33 has been expressed in the smooth muscles and basement membranes in asthmatics as such expression has not been detected in the normal control subjects [87]. Thus, ADAM-33 might also be an indicator concerning diagnostic, severity and possible corticosteroid treatment failure/resistance [111]. Similar to MMP8, according to Simpson et al. [112], SNPs in ADAM33 could influence lung function in early life, and epithelial mesenchymal dysfunction in the airways may predispose individuals toward asthma, being present in early childhood before it becomes clinically expressed [88]. ADAM-33 has been found to be ubiquitously expressed in fetal tissue (8-12 weeks after gestation) as a requirement for proper lung development [111].

In a study conducted by Davies et.al. [113], the level of soluble ADAM-33 has been found to be increased in the airways of asthmatic patients independent of corticosteroid treatment or the airway inflammatory cell profile. In the same study, suppression of remodeling and inflammation in Adam33-null mice after allergen challenge has been reported. The authors highlight the therapeutic potential of targeting ADAM-33 showing that airway remodeling induced by soluble ADAM-33 is reversible [113].

All these data suggest the important role of ADAM 33 in pathogenesis and progression of bronchial asthma, which determines the need of more comprehensive studies in this field. The discovery of the exact impact of each particular SNP in ADAM 33 in different populations will be helpful in prediction and early diagnosis of asthma.

Conclusions

Chronic lung diseases are only one example of the MMP and ADAM activity and yet they show a huge diversity in their functions and their complexity. Their activities are crucial for the proper function of the organism and yet a small alteration in the concentration might lead to severe diseases. Nowadays, it is clear that research in this area is needed since many questions are unsolved. Understanding the role and assessing the genetic variants and expression of MMPs and ADAMs would be a valuable part of personalized medicine. The vast majority of studies on MMP-8 and ADAM-33 in bronchial asthma prove that they can be used as powerful biomarkers for development and progression of the disease. Analyzing them could be useful in clinical practice to improve the healthcare for each individual patient on a personalized basis. Considering the diverse functions of MMP-8 and ADAM-33 in Bronchial asthma, as well as in many other diseases, invention of proper inhibitors of these might be useful tools in the treatment approaches. However, until now many attempts in inventing a novel MMP inhibitor have failed as severe side effects have appeared. A lot of knowledge has yet to be gained about these enzymes since some mechanisms were unknown or not discovered yet.

Acknowledgments

The authors are grateful to Hristina Petrova (Department of Medical Chemistry and Biochemistry, Medical Faculty, Trakia University, Stara Zagora, Bulgaria) for her technical support.

Disclosure statement

The authors declare no conflicts of interest.

Additional information

Funding

This work was supported by the Medical Faculty, Trakia University, Stara Zagora under Grant 8/2021, and by the Bulgarian Ministry of Education and Science (MES) within the frame of the Bulgarian National Recovery and Resilience Plan, Component Innovative Bulgaria, under Grant № BG-RRP-2.004-0006-C02 Development of research and innovation at Trakia University in service of health and sustainable well-being.