132 Chapter 6 organization and structure of the ECM consequently impact the biomechanics of the lung tissue at both the macro and microscales; influencing the biomechanics of breathing and gas exchange but also local forces and mechanotransduction experienced at the cellular level. Asthma The main characteristics of asthma include chronic inflammation and airway hyperresponsiveness, accompanied by airway remodeling which includes goblet cell hyperplasia [19-22]). Changes in the ECM structure in asthma include thickening of the basement membrane and increased deposition of ECM in and around the airway smooth muscle (ASM) layers. These changes have been summarized elegantly elsewhere [8, 22-27] and the complete details are outside the scope of this chapter. Specifically, fibronectin and (fragments of) elastic fibers have been found to be increased in the ASM layer in clinically severe asthma patients, compared to controls [20]. Similarly, the ASM layer contains less proteoglycans in severe asthma patients compared to patients with moderate asthma [28]. In addition, the collagen type IV in basement membrane has also been shown to decrease in asthma patients, despite the increase of the basement membrane thickness [29]. Interestingly, tumstatin, the degradation product of collagen type IV α3, was found to be absent in the lungs of asthma patients, compared to healthy controls [30]. Fibrillar collagen organization was also found to be disorganized in the airways of asthma patients, compared with healthy controls [31]. Higher levels of periostin were found both in the epithelial and subepithelial layers in asthma patients in comparison to controls [32]. Next to the deposited factors, soluble ECM proteins are contributors to the changes in ECM in asthma: Higher levels of Fibulin-1, a secreted glycoprotein, were found in asthma patients compared to the healthy controls [33] and the presence of this glycoprotein in the ECM was important for the regulation of ASM proliferation [33] and the development of airway wall fibrosis [34]. Considered together, these studies illustrate an altered ECM composition in the asthmatic airway wall. Chronic Obstructive Pulmonary Disease (COPD) COPD is a chronic lung disease characterized by airway obstruction caused by several factors including pulmonary inflammation accompanied by bronchitis, mucus hypersecretion, remodeling of the small airway wall and emphysema [35]. The last two phenotypes, airway wall remodeling and emphysema, are the consequences of the alteration of the lung ECM homeostasis [22, 23, 27]. Emphysema is caused by the degradation of elastic fibers and collagens by proteolytic enzymes, including matrix metalloproteinases (MMPs) and elastase [22]. Samples from different origins including sputum, bronchoalveolar lavage, lung parenchyma and lung cells showed
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