Extracellular matrix components and regulators in the airway smooth muscle in asthma

Abstract

There is an intimate relationship between the extracellular matrix (ECM) and smooth muscle cells within the airways. Few studies have comprehensively assessed the composition of different ECM components and its regulators within the airway smooth muscle (ASM) in asthma.With the aid of image analysis, the fractional areas of total collagen and elastic fibres were quantified within the ASM of 35 subjects with fatal asthma (FA) and compared with 10 nonfatal asthma (NFA) patients and 22 nonasthmatic control cases. Expression of collagen I and III, fibronectin, versican, matrix metalloproteinase (MMP)-1, -2, -9 and -12 and tissue inhibitor of metalloproteinase-1 and -2 was quantified within the ASM in 22 FA and 10 control cases.In the large airways of FA cases, the fractional area of elastic fibres within the ASM was increased compared with NFA and controls. Similarly, fibronectin, MMP-9 and MMP-12 were increased within the ASM in large airways of FA cases compared with controls. Elastic fibres were increased in small airways in FA only in comparison with NFA cases.There is altered extracellular matrix composition and a degradative environment within the airway smooth muscle in fatal asthma patients, which may have important consequences for the mechanical and synthetic functions of airway smooth muscle. It has previously been demonstrated that ASM cells exposed to serum from patients with asthma produce increased levels of ECM proteins [6]. In turn, ECM proteins are able to affect the proliferative and secretory state of the ASM [7]. ASM cells secrete matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) [8], which have a role in the immunomodulatory mechanisms regulating ECM composition in asthma patients.In asthma patients, abnormal deposition of ECM elements has been described in the submucosal and adventitial areas of large and small airways [9][10][11][12]. The fractional area of the ECM has also been shown to be increased within the ASM layer in fatal asthma (FA) cases [13], but there are important reasons for better understanding of this subject. First, changes in the ECM composition within the ASM may affect its contractile properties. Digestion with collagenase of the ECM associated with ASM results in increased force generation and shortening in strips of ASM

Transcriptome sequencing (RNA-Seq) of human endobronchial biopsies: asthmaversuscontrols

“…As the degree of airway wall remodelling and inflammation in asthma can vary with location in the tracheobronchial tree and with asthma severity [32], it is possible that gene expression profiles of the peripheral airways and in patients with more severe asthma could turn out to be different from those observed in the present study. Subsequent studies focusing on these locations of the airways in asthma patients with more severe disease are needed to complement our current data in order to provide a more comprehensive overview of the gene expression of the asthmatic airways.…”

Effects of formoterol-budesonide on airway remodeling in patients with moderate asthma

“…In our study, there were increased levels of MMP-9, TIMP-1, and TGF-β 1 as well as a tendency for a higher After treatment with formoterol-budesonide, the levels of the increased cytokines decreased significantly. The counts of neutrophils and eosinophils reflect the degree of chronic inflammation, while the levels of TGF-β 1 , MMP-9, and TIMP-1 reflect the degree of airway remodeling [3][4][5][6] . TGF-β 1 is a 25-kDa homologous molecular dimer that can promote fibroblasts to differentiate into myofibroblasts, which can then secrete interstitial collagen [17] .…”

“…In the state of asthma, too much MMP is generated, leading to an imbalance of MMP/TIMP, excessive degradation of extracellular matrix, and the imbalance of degradation/synthesis, causing structural damage to lung tissue and airway remodeling. MMP-9 and TIMP-1 are the most important factors involved in this process [19] . In our study, we found that there were increased levels of MMP-9, TIMP-1, and TGF-β 1 and a tendency for a higher MMP-9/TIMP-1 ratio in patients with asthma, as well as clinical symptoms and hyper-responsiveness in the airway.…”

“…In asthmatic airways, in situ hybridization and immunohistochemical studies indicate that TGF-β 1 is increased and associated predominantly with submucosal and inflammatory cells, including fibroblasts, smooth muscle cells, eosinophils, macrophages, and the airway ECM, with variable expression associated with epithelial cells [18] . Matrix metalloproteinase (MMP) is the main rate-limiting enzyme that regulates the extracellular matrix [19] . In the state of asthma, too much MMP is generated, leading to an imbalance of MMP/TIMP, excessive degradation of extracellular matrix, and the imbalance of degradation/synthesis, causing structural damage to lung tissue and airway remodeling.…”

“…Epithelial shedding, goblet cell and submucosal gland hyperplasia, increased accumulation of smooth muscle bundles and extracellular matrix (ECM), microvascular alterations, cartilage changes, and airway wall edema are the main histological features of asthmatic airways [2] . The ECM remains in a state of dynamic equilibrium of new synthesis and degradation due to the action of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) [3] as well as growth factors such as transforming growth factor β 1 (TGF-β 1 ) [4] . Of the MMP family, MMP-9 is one of the major proteinases involved in airway inflammation and bronchial remodeling in asthma [5,6] .…”