Bench-to-bedside review: the role of glycosaminoglycans in respiratory disease

Abstract

The extracellular matrix (ECM) plays a significant role in the mechanical behaviour of the lung parenchyma. The ECM is composed of a three-dimensional fibre mesh that is filled with various macromolecules, among which are the glycosaminoglycans (GAGs). GAGs are long, linear and highly charged heterogeneous polysaccharides that are composed of a variable number of repeating disaccharide units. There are two main types of GAGs: nonsulphated GAG (hyaluronic acid) and sulphated GAGs (heparan sulphate and heparin, chondroitin sulphate, dermatan sulphate, and keratan sulphate). With the exception of hyaluronic acid, GAGs are usually covalently attached to a protein core, forming an overall structure that is referred to as proteoglycan. In the lungs, GAGs are distributed in the interstitium, in the sub-epithelial tissue and bronchial walls, and in airway secretions. GAGs have important functions in lung ECM: they regulate hydration and water homeostasis; they maintain structure and function; they modulate the inflammatory response; and they influence tissue repair and remodelling. Given the great diversity of GAG structures and the evidence that GAGs may have a protective effect against injury in various respiratory diseases, an understanding of changes in GAG expression that occur in disease may lead to opportunities to develop innovative and selective therapies in the future.

Figure 1

Schematic structure of glycosaminoglycan and proteoglycan. Note that the hyaluronic acid is not linked to a protein core. Heparan sulphate, dermatan sulphate and chondroitin sulphate are connected to proteoglycan via a serine residue.

Figure 2

Extracellular matrix components in lung parenchyma. CS, chondroitin sulphate; DS, dermatan sulphate; HS, heparan sulphate.

Figure 3

Changes in extracellular matrix. Illutrated are changes in the extracellular matrix that occur during hydraulic and lesional oedemas in spontaneous breathing (SB) and physiological and injurious mechanical ventilation (MV) early and late in the course of lung injury. Bold lines represent the new synthesis of heparan sulphate (HS)-proteoglycan (PG) or chondroitin sulphate (CS)-PG. During hydraulic oedema and in the early phase, the prevalent lesion is fragmentation of CS, whereas in the lesional oedema HS is damaged. In physiological MV, mainly CS-PG was fragmented, but the ongoing MV yields the fragmentation of both glycosaminoglycans. During injurious MV, although HS-PG and CS-PG are injured, collagen fibre content increases early and late in the course of lung injury. Thus, we hypothesize that in the early phase of lung injury collagen fibre synthesis could be beneficial in avoiding the rupture of glycosaminoglycans, minimizing interstitial oedema formation. Pi, interstitial pressure; W/D, wet weight:dry weight ratio.