ASSOCIATION OF THE MMP7 –181A>G PROMOTER
POLYMORPHISM WITH EARLY ONSET OF
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Tacheva T1,*, Dimov D2, Anastasov A1, Zhelyazkova Y2,
Kurzawski M3, Gulubova M4, Drozdzik M3, Vlaykova T1
*Corresponding Author: Assistant Professor Tanya Tacheva, Department of Chemistry and Biochemistry, Medical Faculty,
Trakia University, 11 Armeiska Str., Stara Zagora, Bulgaria. Tel: +359878334176. E-mail: tanya.ta4eva@abv.bg
page: 59
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INTRODUCTION
Chronic obstructive pulmonary disease (COPD) is a
preventable and treatable disease with some significant extrapulmonary
effects that may contribute to its severity in individual
patients. Its pulmonary component is char-acterized
by airflow limitation that is not fully reversible. The airflow
limitation is associated with an abnormal inflammatory response
of the lung to noxious particles or gases [1].
Smoking is one of the main risk factors for COPD,
but since not all smokers develop COPD, as well as the
fact that the disease often develops in middle age, it is
suggested that other factors may play a role in the pathogenesis
such as genetic factors [2]. Inhalation of cigarette
smoke, organic and/or inorganic dust, chemical agents and
particle matters increase the risk of developing COPD. The
presence of these irritants, may lead to chronic inflammation
and structural changes in the lung due to repeated
injury and repair [3]. Pathological changes characteristic
for COPD are found in the proximal airways, peripheral
airways, lung parenchyma and pulmonary vasculature [4].
One of the main roles of the epithelial cells is to
provide a barrier against pathogens and to release antimicrobial
products. By producing chemoattractants and adhesion
molecules, epithelial cells contribute to the migration
of the inflammatory cells to injury sites [5,6]. Epithelial damage is an important characteristic of several pulmonary
diseases including COPD. Numerous enzymes, proteins
and peptides are involved in the process of tissue repair
and remodeling [7].
The matrix metalloproteinases (MMPs) family is
composed of more than 25 zinc-dependent proteases that
cleave the extracellular matrix and cell-surface proteins
to regulate wound healing, physiological angiogenesis
and immune response [8]. Matrix metalloproteinases can
activate and increase the bioavailability of a variety of
non matrix proteins, including cytokines, chemokines,
recep-tors and antimicrobial peptides [5,9]. Matrilysin
1 (MMP-7), unlike many MMPs, is expressed by non
injured, non inflamed mucosal epithelia in most adult human
tissues (7). Besides extracellular matrix (ECM) components,
MMP-7 processes cell surface molecules such as
pro-defensin, Fas-ligand, pro-tumor necrosis factor (TNF),
and E-cadherin [10,11].
The production of the enzyme is highly up-regulated
by injury or exposure to bacteria, stimulating cell migration
and coordinating the inflammatory response [12-14].
Thus, MMP-7 participates in the processes of defense,
repair and inflammation.
In the promoter of the gene of MMP-7 an A>G transition
has been identified as a functional polymorphism
(MMP7 –181A>G; rs11568818). The polymorphism has
been shown to modulate transcriptional activity by influencing
the binding of nuclear regulatory proteins. The G
allele has greater basal transcriptional activity than the A
allele in vitro experiment in the human monocyte/ macrophage
cell line U937 [15]. The nuclear proteins bind with
higher affinity to the G allele than to the A allele, resulting
in significant increase in promoter activity [16,17].
So far, there are only very limited studies concerning
the role of MMP-7 and its genetic variants in lung
diseases such as lung cancer [18], pneumoconiosis [19],
bron-chiolitis obliterans syndrome (BOS) in patients after
lung transplantation [20], and idiopathic pulmonary
fibrosis (IPF) [21]. Concerning COPD, there was only
one report showing increased serum level of MMP-7 in
patients exposed to biomass and tobacco smoke compared
with non smoking healthy controls, and the levels were
negatively correlated with spirometric index of lung function
(FEV1 %pr.) [22]. However, there has only been one
study exploring the functional variants of MMP-7 in the
development of COPD [23].
In this respect we aimed to evaluate the possible role
of the MMP7 –181A>G promoter polymorphism as predisposing
factor for COPD in a population from the region
of Stara Zagora, Bulgaria.
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