title: 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.
authors.affiliation: Department of Experimental Medical Sciences, Lund University, Sweden.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Westergren-Thorsson
authors.affiliation: Department of Experimental Medical Sciences, Lund University, Sweden; AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Hedström
authors.affiliation: Department of Experimental Medical Sciences, Lund University, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Nybom
authors.affiliation: Department of Experimental Medical Sciences, Lund University, Sweden.
authors.forename: Emil
authors.initials: E
authors.lastname: Tykesson
authors.affiliation: Department of Experimental Medical Sciences, Lund University, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Åhrman
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Hornfelt
authors.affiliation: Department of Experimental Medical Sciences, Lund University, Sweden.
authors.forename: Marco
authors.initials: M
authors.lastname: Maccarana
authors.affiliation: Department of Biochemistry, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.affiliation: Department of Cardiothoracic Surgery, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Dellgren
authors.affiliation: Department of Experimental Medical Sciences, Lund University, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Wildt
authors.affiliation: AstraZeneca R&D, Mölndal, Sweden.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Zhou
authors.affiliation: Department of Experimental Medical Sciences, Lund University, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Eriksson
authors.affiliation: Department of Respiratory Medicine and Allergology, Lund University, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Bjermer
authors.affiliation: Department of Experimental Medical Sciences, Lund University, Sweden; Department of Respiratory Medicine and Allergology, Lund University, Sweden,. Electronic address: oskar.hallgren@med.lu.se.
authors.forename: Oskar
authors.initials: O
authors.lastname: Hallgren
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002809:Chondroitin Sulfates / Q000378:metabolism; D003871:Dermatan Sulfate / Q000031:analogs & derivatives / Q000378:metabolism; D004187:Disaccharides / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006025:Glycosaminoglycans / Q000378:metabolism*; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D015238:Sulfotransferases / Q000378:metabolism
chemical_list: D002809:Chondroitin Sulfates; D003871:Dermatan Sulfate; D004187:Disaccharides; D006025:Glycosaminoglycans; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D006909:Hydroxyproline; D015238:Sulfotransferases; C069524:dermatan sulfate chondroitin sulfate; C071927:perlecan
keywords: Chondroitin sulfate; Collagen; Glycosaminoglycan; Heparan sulfate; Idiopathic pulmonary fibrosis