Increased deposition of glycosaminoglycans and altered structure of heparan sulfate in idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant deposition of extracellular matrix (ECM) constituents, including glycosaminoglycans (GAGs), that may play a role in remodelling processes by influencing critical mediators such as growth factors. We hypothesize that GAGs may be altered in IPF and that this contribute to create a pro-fibrotic environment. The aim of this study was therefore to examine the fine structure of heparan sulfate (HS), chondroitin/dermatan sulfate (CS/DS) and hyaluronan (HA) in lung samples from IPF patients and from control subjects. GAGs in lung samples from severe IPF patients and donor lungs were analyzed with HPLC. HS was assessed by immunohistochemistry and collagen was quantified as hydroxyproline content. The total amount of HS, CS/DS and HA was increased in IPF lungs but there was no significant difference in the total collagen content. We found a relative increase in total sulfation of HS due to increment of 2-O, 6-O and N-sulfation and a higher proportion of sulfation in CS/DS. Highly sulfated HS was located in the border zone between denser areas and more normal looking alveolar parenchyma in basement membranes of blood vessels and airways, that were immuno-positive for perlecan, as well as on the cell surface of spindle-shaped cells in the alveolar interstitium. These findings show for the first time that both the amount and structure of glycosaminoglycans are altered in IPF. These changes may contribute to the tissue remodelling in IPF by altering growth factor retention and activity, creating a pro-fibrotic ECM landscape.

Targeting TGF-β Mediated SMAD Signaling for the Prevention of Fibrosis

“…HSPGs are upregulated in many human fibrotic conditions, including human idiopathic lung fibrosis (Jiang et al, 2010; Westergren-Thorsson et al, 2017), Duchenne’s Muscular Dystrophy (Alvarez et al, 2002), liver disease (Roskams et al, 1996) and kidney fibrosis (Ebefors et al, 2011). Additionally, heparanase, the enzyme that metabolizes the carbohydrate chains on these proteoglycans, is also upregulated in fibrotic pathologies (Lv et al, 2016).…”

The dual role of the glycosaminoglycan chondroitin‐6‐sulfate in the development, progression and metastasis of cancer

“…Interestingly, the mature osteoarthritis cartilage contains CS with an especially high level of 6‐ O ‐sulfation , which could functionally compensate for the loss of a GAG that has such a composition in the disease‐affected tissue areas. An increased content of 6‐ O ‐sulfated CS disaccharides and an elevated deposition of CS/DS have also been shown to characterize the tissue remodeling that is associated with fibrosis . However, in contrast to the metabolic changes of CS/DS in the tumor microenvironment, in the fibrosis‐affected tissues there is also a proportional elevation of the 4‐ O ‐sulfation in CS/DS so that the normal ratio between the 6‐ O ‐ and 4‐ O ‐sulfated disaccharides is preserved in these GAGs .…”

“…An increased content of 6‐ O ‐sulfated CS disaccharides and an elevated deposition of CS/DS have also been shown to characterize the tissue remodeling that is associated with fibrosis . However, in contrast to the metabolic changes of CS/DS in the tumor microenvironment, in the fibrosis‐affected tissues there is also a proportional elevation of the 4‐ O ‐sulfation in CS/DS so that the normal ratio between the 6‐ O ‐ and 4‐ O ‐sulfated disaccharides is preserved in these GAGs . Interestingly, a recent study using an animal model of lung fibrosis showed that substantial alterations in the CS/DS metabolism begin in the inflammatory phase of this process and that they are regulated by TGFβ1, which also plays a crucial role in the tumor progression .…”

Proteoglycans as Immunomodulators of the Innate Immune Response to Lung Infection

“…[8][9][10] In healthy adult human lungs, the total amounts of chondroitin sulfate/dermatan sulfate (CS/DS), HA, and HS were found to be equal. 11 Not as much is known about the importance of CS, DS, or keratan sulfate (KS) PGs in lung morphogenesis. There is evidence that the amount of CS progressively diminishes during development especially in the lung parenchyma.…”