ECM remodeling is a delicate equilibrium and a prerequisite for maintenance of a healthy tissue in which old proteins are continuously degraded and new proteins are formed.40 This delicate balance is disturbed in connective tissue diseases, resulting in an increased turnover of both formation and degradation in the peripheral airway wall, leading to tissue disruption and fibrosis.41,42 COPD is, to a large extent, a connective tissue disease that may, in part, be described as an uncontrolled damage-repair process resulting from chronic inflammation. This leads to an imbalanced tissue turnover, accumulation of ECM proteins,34 and altered tissue remodeling, which finally results in loss of tissue function and, eventually, organ failure. It has been proposed that persistent injury to the lung epithelium drives a process known as the epithelial-to-mesenchymal transition in which transforming growth factor-β overexpression directs epithelial cell transdifferentiation into a mesenchymal cell and then to a myofibroblast during lung wound healing.41,43 Epithelial-to-mesenchymal transition is believed to be a key factor during airway remodeling and fibrosis development; however, resident fibroblasts, α-smooth muscle cells, and fibrocytes are also reported to differentiate into myofibroblasts during the process. Myofibroblasts are able to produce and deposit ECM proteins, especially collagens, as well as regulate the tissue turnover balance by secretion of matrix metalloproteinases (MMPs).41,43 It has been demonstrated in patients with COPD that the airway wall composition is changed compared with healthy individuals, resulting in increased deposition of collagens type I and III; fibronectin; laminin44,45; and the proteoglycans versican, biglycan, decorin, and perlecan,46 all of which allegedly have severe effects on lung integrity and ability to recoil. A subset of pathologic proteases has been reported to be overexpressed in COPD-affected tissue, such as elastase47 and MMP-1, -2, -7, and -12,48 most of which possess collagenolytic activity. This results in the release of protease-specific fragments of such signature proteins. It is well recognized that in emphysema, in addition to degradation of elastin in alveoli, collagens are degraded,45 thus generating elastin and collagen fragments expected to be released into systemic circulation.