Increased deposition of chondroitin/dermatan sulfate glycosaminoglycan and upregulation of β1,3-glucuronosyltransferase I in pulmonary fibrosis

Abstract

Pulmonary fibrosis (PF) is characterized by increased deposition of proteoglycans (PGs), in particular core proteins. Glycosaminoglycans (GAGs) are key players in tissue repair and fibrosis, and we investigated whether PF is associated with changes in the expression and structure of GAGs as well as in the expression of β1,3-glucuronosyltransferase I (GlcAT-I), a rate-limiting enzyme in GAG synthesis. Lung biopsies from idiopathic pulmonary fibrosis (IPF) patients and lung tissue from a rat model of bleomycin (BLM)-induced PF were immunostained for chondroitin sulfated-GAGs and GlcAT-I expression. Alterations in disaccharide composition and sulfation of chondroitin/dermatan sulfate (CS/DS) were evaluated by fluorophore-assisted carbohydrate electrophoresis (FACE) in BLM rats. Lung fibroblasts isolated from control (saline-instilled) or BLM rat lungs were assessed for GAG structure and GlcAT-I expression. Disaccharide analysis showed that 4- and 6-sulfated disaccharides were increased in the lungs and lung fibroblasts obtained from fibrotic rats compared with controls. Fibrotic lung fibroblasts and transforming growth factor-β(1) (TGF-β(1))-treated normal lung fibroblasts expressed increased amounts of hyaluronan and 4- and 6-sulfated chondroitin, and neutralizing anti-TGF-β(1) antibody diminished the same. TGF-β(1) upregulated GlcAT-I and versican expression in lung fibroblasts, and signaling through TGF-β type I receptor/p38 MAPK was required for TGF-β(1)-mediated GlcAT-I and CS-GAG expression in fibroblasts. Our data show for the first time increased expression of CS-GAGs and GlcAT-I in IPF, fibrotic rat lungs, and fibrotic lung fibroblasts. These data suggest that alterations of sulfation isomers of CS/DS and upregulation of GlcAT-I contribute to the pathological PG-GAG accumulation in PF.

The Transforming Growth Factor-Beta Signaling Pathway Involvement in Cardiovascular Lesions in Mucopolysaccharidosis-I

“…Although the primary cause of TGF-b hyperactivity in the cardiovascular lesions in a patient with MPS-I is unclear, increased TGF-b activity is known to up-regulate beta1,3-glucuronosyltransferase-I in fibroblasts, a rate-limiting enzyme in glycosaminoglycan synthesis, which leads to increase synthesis of glycosaminoglycans including dermatan sulfate, hyaluronic acid, and chondroitin sulfate A and C (Venkatesan et al 2011;Matalon and Dorfman 1968). It is also known that accumulated dermatan sulfate can activate STAT proteins which increase productions of elastindegrading proteins, i.e., matrix metalloproteinase-12 (MMP-12) and cathepsin S. (Ma et al 2008).…”

Interplay of extracellular matrix and leukocytes in lung inflammation

“…Evidence from both animal and human cell culture models has demonstrated that modulation of hyaluronan occurs in the setting of infection and/or viral mimetics [84, 179]. Hyaluronan levels in lung tissue and bronchoalveolar lavage fluid (BALF) are elevated and correlate with the degree of inflammation in animal models of lung injury [139, 180, 181]. Furthermore, concentration of airway hyaluronan is higher in asthmatics and correlates with asthma severity [105, 134, 135, 138].…”

Matrix Remodeling in Pulmonary Fibrosis and Emphysema

“…The PGs normally contribute to the mechanical stability of the collagen-elastin network and prevent collapse of alveolar structures caused by electrostatic interactions from the negatively charged GAGs (81). Structural remodeling of the lung resulting from abnormal expression of PG-GAG complexes and structural changes to the GAG side chains can contribute to the development of pulmonary diseases (45,(83)(84)(85)(86)(87)(88).…”