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Antiproliferative heparan sulfate inhibiting hyaluronan and transforming growth factor-β expression in human lung fibroblast cells

A possible antifibrotic therapy?

Clinical Proteomics volume 1, pages 271–284 (2004)Cite this article

Abstract

The objective of this study was to examine the effects of heparan sulfate (HS) on factors involved in the remodeling of connective tissue observed in patients with fibrotic respiratory disorders such as asthma. A suitable working model is to stimulate human fetal lung fibroblasts in vitro with structurally different forms of HS. Highly sulfated and iduronic acid (IdoUA)-rich HS specifically decreased cell proliferaton, production of jyaluronan (HA), transforming growth factor (TGF)-β1, and TFF-β-induced α-smooth muscle actin but did not affect the overall proteoglycan production in the cells. These repressed factors are suggested to play a critical role in the early stages of remodeling and myofibroblast activation. Low sulfated and IdoUA-poor HS did not display any effects on these factors. Furthermore, analysis of the protein expression pattern by two-dimensional gel electrophoresis revealed a 70% increased expression of annexin II, which has previously been shown to have a high affinity for both heparin and HS. Heat-shock protein 27 and arsenite translocating factor, both involved in actin organization and polymerization, were also increased in the HS-stimulated cells. Thus, the reduced expression of HA and TGF-β1, both important in the development of fibrosis, seems to be mediated by pecific changes in protein expression of the fibroblast. The observed inhibition of cell proliferation, HA, and TGF-β1 allows speculation of highly sulfated HS as a antifibrotic candidate in the early stage of remodeling.

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Authors and Affiliations

  1. Respiratory Medicine and Allergology, Lund University Hospital, Lund, Sweden

    Ellen Tufvesson

  2. Analytical Chemistry, Lund University, Lund, Sweden

    György Marko-Varga

  3. Experimental Medical Science, Division of Vascular and Airway Research, Lund University, BMC C13, S-221 84, Lund, Sweden

    Kristoffer Larsen, Johan Malmström & Gunilla Westergren-Thorsson

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  1. Kristoffer Larsen
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  2. Johan Malmström
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  5. Gunilla Westergren-Thorsson
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Correspondence to Kristoffer Larsen.

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Larsen, K., Malmström, J., Tufvesson, E. et al. Antiproliferative heparan sulfate inhibiting hyaluronan and transforming growth factor-β expression in human lung fibroblast cells. Clin Proteom 1, 271–284 (2004). https://doi.org/10.1385/CP:1:3-4:271

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Clinical Proteomics

ISSN: 1559-0275