Matrix metalloproteinases in asthma and COPD

doi:10.1016/j.coph.2004.12.005

Current Opinion in Pharmacology

Volume 5, Issue 3, June 2005, Pages 257-263

https://doi.org/10.1016/j.coph.2004.12.005 Get rights and content

Asthma and chronic obstructive pulmonary disease (COPD) are both highly prevalent, chronic inflammatory lung diseases that lead to significant morbidity and mortality. Matrix metalloproteinases (MMPs) are extracellular matrix degrading enzymes that play a critical role in normal development and physiological tissue remodeling and repair. In addition, they play an important role in the regulation of the kinetics and function of inflammatory cells. There is increasing evidence that MMPs are involved in the pathogenesis of both asthma and COPD, and several MMPs are possible therapeutic targets in these common chronic airway diseases.

Introduction

Matrix metalloproteinases (MMPs) are proteolytic enzymes that are able to degrade extracellular matrix (ECM) components, and thus play a role in cell migration and tissue remodeling. Moreover, they can splice and (in)activate cytokines and chemokines, thereby influencing the recruitment and function of inflammatory cells [1^••].

Chronic obstructive pulmonary disease (COPD) and asthma are both chronic lung diseases that share some features, and yet are quite different disease entities. COPD is mainly caused by inhalation of cigarette smoke, resulting in irreversible airflow limitation, whereas asthma is characterized by an allergic reaction in the airways, leading to reversible airflow obstruction.

A common feature of both diseases is the chronic inflammation in the airways (influx of inflammatory cells into the lung) and the development of extensive tissue remodeling during the course of the disease process. In some cases, especially in COPD, this remodeling causes destruction of healthy lung tissue, leading to emphysema. For this reason, there is increased interest in the role of MMPs in asthma and COPD: MMPs probably contribute to the migration of inflammatory cells into the lung, as well as to the remodeling, and sometimes even destruction, of lung tissue.

Here, we describe the most recent data on the role of MMPs in asthma and COPD. We focus on findings from studies on human subjects rather than from animal models, and discuss the possibility of targeting MMPs as a new therapeutic approach in the management of asthma and COPD.

Section snippets

Biology of matrix metalloproteinases

MMPs are part of a large metalloendopeptidase superfamily. They typically consist of a pro-domain and a catalytic domain. The latter contains a zinc ion in the active site, as well as a characteristic methionine turn, which is caused by a conserved methionine residue downstream of the zinc binding site. To date, 24 MMPs have been identified in mammals; cellular sources include inflammatory, stromal and epithelial cells. Some MMPs are anchored to the cell surface, whereas others are secreted

Possible pathogenetic mechanisms

There are many ways in which MMPs are likely to participate in the disease process of both asthma and COPD (Figure 1). MMPs might contribute to the breakdown of ECM, resulting in the destruction of healthy lung parenchyma. During this process, chemotactic fragments are generated from the degraded ECM, attracting inflammatory cells into the damaged tissue. It is also possible that ECM breakdown releases chemokines that are otherwise ‘trapped’ in the ECM. Several MMPs affect the activity of

MMPs and asthma

Patients with asthma have an increased gelatinolytic activity linked to MMP-2 and MMP-9 and higher levels of tissue inhibitor of metalloproteinase-1 (TIMP-1; a natural inhibitor of MMPs) in their sputum [3]. The activated form of MMP-9 (85 kDa) was found in the sputum from 60% of asthmatics, but was absent from that of control subjects. Although less frequently detectable than pro-MMP-9 (pro-MMPs are catalytically inactive and are activated into the active MMP after cleaving of the pro-domain),

MMPs and COPD

Recent studies in human subjects provide increasing evidence for a role of MMPs in COPD. Patients with COPD have an increased gelatinolytic activity in sputum linked to MMP-2 and MMP-9 [3]. The activated form of MMP-9 (85 kDa) was found in the sputum from 85% of COPD patients, but was absent from that of control subjects, whereas pro-MMP-2 (72 kDa) was found in 25% of COPD patients and in only 5% of controls. Levels of TIMP-1 were higher in COPD patients than in controls. These findings were

Inhibitors of MMPs

TIMPs are natural inhibitors of MMPs, which they can inhibit by binding to the catalytic site of MMPs. Four different TIMPs are known today (TIMP-1, -2, -3 and -4), and they inhibit all MMPs tested so far (except for TIMP-1, which fails to inhibit MT1-MMP). However, there are differences in the affinity for specific MMPs (e.g. TIMP-3 is a more potent inhibitor of MMP-9 than other MMPs) [30].

It seems logical to use these endogenous antiproteinases in the treatment of asthma and COPD. Indeed, we

Conclusions

There is increasing evidence that MMPs are involved in the pathogenesis of asthma and COPD. Further exploration of the role of MMPs in these highly prevalent diseases is crucial to identify which are possible therapeutic targets. MMP-9, but perhaps also MMP-1, -2, -8 and -12, seem to be good candidates.

As mentioned previously, MMPs have many diverse functions and it is clear that interference with these functions could not only have beneficial effects (e.g. reduced destruction of lung tissue;

Update

Very recently, Molet et al. [33^••] reported enhanced MMP-12 levels in BAL fluid from COPD patients compared with that from controls. Moreover, the number of MMP-12-expressing macrophages in BAL, as well as in tissue sections from bronchial biopsies, was higher in COPD patients. These data underscore the importance of MMP-12 in the development of COPD.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

We would like to dedicate this review to the memory of Prof Romain Pauwels, whose scientific and clinical experience was of great inspiration to all of us involved in the field of respiratory medicine and research.

This work was supported by the Fund for Scientific Research in Flanders (FWO Vlaanderen, Research Project G. 30001103 and G.0343.01N), by Project Grant 01251504 from the Concerted Research Initiative of the Ghent University and by the Institute for the promotion of Innovation by

References (34)

M.E. Boulay et al.
Metalloproteinase-9 in induced sputum correlates with the severity of the late allergen-induced asthmatic response
Respiration
(2004)
H.S. Park et al.
Metalloproteinase-9 is increased after toluene diisocyanate exposure in the induced sputum from patients with toluene diisocyanate-induced asthma
Clin Exp Allergy
(2003)
M. Cundall et al.
Neutrophil-derived matrix metalloproteinase-9 is increased in severe asthma and poorly inhibited by glucocorticoids
J Allergy Clin Immunol
(2003)
E.A. Kelly et al.
Increased matrix metalloproteinase-9 in the airway after allergen challenge
Am J Respir Crit Care Med
(2000)
S.E. Wenzel et al.
Subepithelial basement membrane immunoreactivity for matrix metalloproteinase 9: association with asthma severity, neutrophilic inflammation, and wound repair
J Allergy Clin Immunol
(2003)
D.D. Cataldo et al.
Matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases mRNA transcripts in the bronchial secretions of asthmatics
Lab Invest
(2004)
K.Y. Vermaelen et al.
Matrix metalloproteinase-9-mediated dendritic cell recruitment into the airways is a critical step in a mouse model of asthma
J Immunol
(2003)
G.A. Finlay et al.
Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphysematous patients
Thorax
(1997)
G.A. Finlay et al.
Matrix metalloproteinase expression and production by alveolar macrophages in emphysema
Am J Respir Crit Care Med
(1997)
M.J. Kang et al.
Lung matrix metalloproteinase-9 correlates with cigarette smoking and obstruction of airflow
J Korean Med Sci
(2003)

L.M. Coussens et al.

Matrix metalloproteinase inhibitors and cancer: trials and tribulations

Science

(2002)

W.C. Parks et al.

Matrix metalloproteinases as modulators of inflammation and innate immunity

Nat Rev Immunol

(2004)

M.D. Sternlicht et al.

How matrix metalloproteinases regulate cell behavior

Annu Rev Cell Dev Biol

(2001)

D. Cataldo et al.

MMP-2- and MMP-9-linked gelatinolytic activity in the sputum from patients with asthma and chronic obstructive pulmonary disease

Int Arch Allergy Immunol

(2000)

Y.C. Lee et al.

The involvement of matrix metalloproteinase-9 in airway inflammation of patients with acute asthma

Clin Exp Allergy

(2001)

W. Mattos et al.

Matrix metalloproteinase-9 expression in asthma: effect of asthma severity, allergen challenge, and inhaled corticosteroids

Chest

(2002)

D.D. Cataldo et al.

Matrix metalloproteinase-9, but not tissue inhibitor of matrix metalloproteinase-1, increases in the sputum from allergic asthmatic patients after allergen challenge

Chest

(2002)

Cited by (149)

Ex vivo Immuno-modulatory effect of Echinococcus granulosus laminated layer during allergic rhinitis and allergic asthma: A study in Algerian Patients
2023, Experimental Parasitology
The effect of helminthic infections on allergic diseases and asthma is still inconclusive. Moreover, there is considerable evidence suggesting that nitric oxide (NO), metalloproteinases and pro-inflammatory cytokines play a significant role in the physiopathology of these diseases. In this sense, the aim of our study is to investigate the ex vivo immunomodulatory effect of the laminated layer (LL, outside layer of parasitic cyst) of the helminth Echinococcus granulosus on NO, IL-17A and IL-10 production. In the first step of our study, we evaluated in vivo the NO, MMP-9, IL-17A, IL-10 levels in Algerian patients with allergic asthma and allergic rhinitis and their changes in relation with exacerbation status of the patients. In the principal part of our work, we assessed NO, IL-10 and IL-17A levels in supernatants of patients PBMC cultures before and after stimulation with LL. Our results indicate a significant reduction in NO production by PBMC of patients with allergic rhinitis and allergic asthma whether mild, moderate or severe after stimulation with LL. Interestingly, LL induces a significant decrease in the production of NO and IL17-A levels as well as an increase in the production of IL-10 in the cultures performed with PBMC of patients with severe allergic asthma.
Importantly, our data indicate that LL exert a down-modulatory effect on inflammatory mediators (NO, IL-17A) and up immune-regulatory effect on IL-10 production. Collectively, our study supports the hygiene hypothesis suggesting that Echinococcus granulosus infection like other helminths could prevent and/or modulate inflammation responses during inflammatory diseases.
In vitro human cell-based models to study airway remodeling in asthma
2023, Biomedicine and Pharmacotherapy
Airway remodeling, as a predominant characteristic of asthma, refers to the structural changes that occurred both in the large and small airways. These pathological changes not only contribute to airway hyperresponsiveness and airway obstruction, but also predict poor outcomes of patients. In vitro models are the alternatives to animal models that facilitate airway remodeling research. Current approaches to mimic airway remodeling in vitro include mono cultures of cell lines and primary cells that are derived from the respiratory tract, and co-culture systems that consist of different cell subpopulations. Moreover, recent advances in microfluid chips and organoids show promise in simulating the complex architecture and functionality of native organs. According, they enable highly physiological-relevant investigations of human diseases in vitro. Here we aim to detail the current human cell-based models regarding their key pros and cons, and to discuss how they may be used to facilitate our understanding of airway remodeling in asthma.
Role of metalloproteinases and TNF-α in obesity-associated asthma in mice
2020, Life Sciences
Numerous population studies conducted worldwide indicate that the prevalence of asthma is higher in obese versus lean individuals. It has been reported that sensitized lean mice has a better recovery of lung inflammation in asthma. Extracellular matrix (ECM) plays an essential role in the structural support of the lungs regulating the airways diameter, thus preventing its collapse during expiration. ECM renewal by metalloproteinase (MMPs) enzymes is critical for pulmonary biology. There seems to be an imbalance of MMPs activity in asthma and obesity, which can impair the lung remodeling process. In this study, we characterized the pulmonary ECM of obese and lean mice, non-sensitized and sensitized with ovalbumin (OVA). Pharmacological intervention was performed by using anti-TNF-α, and MMP-8 and MMP-9 inhibitors in obese and lean sensitized mice. Activity of MMPs was assessed by gelatinase electrophorese, western blotting and zymogram in situ. Unbalance of MMP-2, MMP-8, MMP-9 and MMP-12 was detected in lung tissue of OVA-sensitized obese mice, which was accompanied by high degradation, corroborating an excessive deposition of types I and III collagen in pulmonary matrix of obese animals. Inhibitions of TNF-α and MMP-9 reduced this MMP imbalance, clearly suggesting a positive effect on pulmonary ECM. Obese and lean mice presented diverse phenotype of asthma regarding the ECM compounds and the inhibition of MMPs pathway could be a good alternative to regulate the activity in ECM lungs of asthmatic obese individuals.
Overexpression of matrix metalloproteinase-9 in adolescents with primary spontaneous pneumothorax for surgical intervention
2018, Journal of Thoracic and Cardiovascular Surgery
To determine gene expression profiles associated with bullae formation in patients with primary spontaneous pneumothorax and to identify candidate genes associated with surgical intervention.
Twenty-four adolescents with primary spontaneous pneumothorax were enrolled prospectively. A global gene expression analysis of 9 paired lung biopsies (lesion and normal adjacent sites) was performed to identify differentially expressed genes associated with spontaneous pneumothorax. Pathway and network analysis was performed using the Database for Annotation, Visualization and Integrated Discovery web tool. Candidate genes and encoding proteins were assessed in blood samples and compared between patients with pneumothorax and healthy control patients.
A total of 1519 differentially expressed transcripts corresponding to known genes were identified comparing the lesion lung with paired adjacent normal lung. The altered genes were mainly associated with focal adhesion and extracellular matrix–receptor interaction pathways. Genes involved in proteolysis and peptidase activity were up-regulated predominantly, especially matrix metalloproteinase-1 and -9 genes. Compared with the recovery stage, blood levels of matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 were increased at the acute stage in patients with pneumothorax and, when compared between patients treated operatively with those treated nonoperatively, were also significantly greater. In addition, ratios of their serum levels were significantly greater in patients with pneumothorax compared with healthy control patients. Furthermore, matrix metalloproteinase-9 was predominantly overexpressed in neutrophils, alveolar macrophages, and mesothelial cells of lung biopsies.
An imbalance of cell–extracellular matrix interactions appears to be associated with primary spontaneous pneumothorax. Matrix metalloproteinase-9 overexpression may particularly play a role in contributing to pleural porosity for surgical intervention.
Assessment of MMP-9 and clinical characteristics in dogs with tracheal collapse based on cough severity and fluoroscopic findings: a cross-sectional study
2024, BMC Veterinary Research
Associations of MMP9 polymorphism with the risk of severe pneumonia in a Southern Chinese children population
2024, BMC Infectious Diseases

View all citing articles on Scopus

View full text

Matrix metalloproteinases in asthma and COPD

Introduction

Section snippets

Biology of matrix metalloproteinases

Possible pathogenetic mechanisms

MMPs and asthma

MMPs and COPD

Inhibitors of MMPs

Conclusions

Update

References and recommended reading

Acknowledgements

Respiration

Clin Exp Allergy

J Allergy Clin Immunol

Am J Respir Crit Care Med

J Allergy Clin Immunol

Lab Invest

J Immunol

Thorax

Am J Respir Crit Care Med

J Korean Med Sci

Science

Matrix metalloproteinases as modulators of inflammation and innate immunity

Nat Rev Immunol

How matrix metalloproteinases regulate cell behavior

Annu Rev Cell Dev Biol

MMP-2- and MMP-9-linked gelatinolytic activity in the sputum from patients with asthma and chronic obstructive pulmonary disease

Int Arch Allergy Immunol

The involvement of matrix metalloproteinase-9 in airway inflammation of patients with acute asthma

Clin Exp Allergy

Matrix metalloproteinase-9 expression in asthma: effect of asthma severity, allergen challenge, and inhaled corticosteroids

Chest

Matrix metalloproteinase-9, but not tissue inhibitor of matrix metalloproteinase-1, increases in the sputum from allergic asthmatic patients after allergen challenge

Chest