The ‘sweet’ and ‘bitter’ involvement of glycosaminoglycans in lung diseases: pharmacotherapeutic relevance

Abstract

The extracellular matrix (ECM) plays a significant role in the structure and function of the lung. The ECM is a three-dimensional fibre mesh, comprised of various interconnected and intercalated macromolecules, among which are the glycosaminoglycans (GAG). GAG are long, linear and highly charged, heterogeneous polysaccharides that are composed of a variable number of repeating disaccharide units (macromolecular sugars) and most of them, as their name implies, have a sweet taste. In the lung, GAG support the structure of the interstitium, the subepithelial tissue and the bronchial walls, and are secreted in the airway secretions. Besides maintaining lung tissue structure, GAG also play an important role in lung function as they regulate hydration and water homeostasis, modulate the inflammatory response and influence lung tissue repair and remodelling. However, depending on their size and/or degree of sulphation, and their immobilization or solubilization in the ECM, specific GAG in the lung either live up to their sweet taste/name, supporting normal lung physiology, or they are associated to 'bitter' effects, related to lung pathology. The present review discusses the biological role of GAG in the lung as well as the involvement of these molecules in various respiratory diseases. Given the great structural diversity of GAG, understanding the changes in GAG expression that occur in lung diseases may lead to novel targets for pharmacological intervention in order to prevent and/or to treat a range of lung diseases.

TSG-6 Protein Is Crucial for the Development of Pulmonary Hyaluronan Deposition, Eosinophilia, and Airway Hyperresponsiveness in a Murine Model of Asthma

“…Increasing evidence now suggests that pulmonary GAGs are also involved in pulmonary inflammation, repair, and pathology (8,9). In this study, we examined the role of TSG-6 during the induction and propagation of antigen-induced pulmonary eosinophilia and AHR.…”

“…GAG components of the pulmonary ECM are integral components of the structural scaffold required for pulmonary development, mechanics, and many processes that contribute to maintaining lung homeostasis (8). Increasing evidence now suggests that pulmonary GAGs are also involved in pulmonary inflammation, repair, and pathology (8,9).…”

“…ECM modifications during inflammatory responses have been shown to influence the distribution, activation, survival, and adhesion of inflammatory cells, and the ECM can act as a reservoir for inflammatory mediators and growth factors (5,6). This is of particular relevance in the asthmatic airways, in which the profile of the ECM is altered (7,8).…”

Dual Role of Toll-Like Receptors in Asthma and Chronic Obstructive Pulmonary Disease

“…Patients suffering from asthma and COPD show increased ECM turnover and increased deposition of ECM components in their lungs (Noble and Jiang, 2006). The role of ECM in health and disease has received a lot of attention in recent years (Teder et al, 2002;Jiang et al, 2007;Papakonstantinou and Karakiulakis, 2009). ECM components are significantly involved in maintaining tissue structure and function of the lung and in the modulation of inflammatory responses.…”

Respiratory Tissue Engineering: Current Status and Opportunities for the Future

“…Smooth muscle cells, fibroblasts, chondrocytes, and inflammatory cells constitute the cellular content, mediating muscle contraction, matrix composition, and signalling processes. Noncellular molecules such as collagen, elastin and various glycosaminoglycans (GAGs) modulate structural support and morphogenesis in tandem with growth factors and morphogens such as epidermal growth factor, bone morphogenetic proteins and fibroblast growth factors (19)(20)(21)(22), which can dictate cell differentiation when engineering an in vitro tissue engineered tracheobronchial model. A continuous network of fibrillar collagen I and III supports the epithelium and airway smooth muscle (20),reinforced by a series of C-shaped cartilage rings located along the outside of the upper respiratory tract.…”