ASSOCIATION OF THE MMP7 181A>G PROMOTER POLYMORPHISM WITH EARLY ONSET OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Tacheva T, Dimov D, Anastasov A, Zhelyazkova Y, Kurzawski M, Gulubova M, Drozdzik M, Vlaykova T
*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
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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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