title: Endothelial and leukocyte heparan sulfates regulate the development of allergen-induced airway remodeling in a mouse model.
abstract: Heparan sulfate (HS) proteoglycans (HSPGs) participate in several aspects of inflammation because of their ability to bind to growth factors, chemokines, interleukins and extracellular matrix proteins as well as promote inflammatory cell trafficking and migration. We investigated whether HSPGs play a role in the development of airway remodeling during chronic allergic asthma using mice deficient in endothelial- and leukocyte-expressed N-deacetylase/N-sulfotransferase-1 (Ndst1), an enzyme involved in modification reactions during HS biosynthesis. Ndst1-deficient and wild-type (WT) mice exposed to repetitive allergen (ovalbumin [OVA]) challenge were evaluated for the development of airway remodeling. Chronic OVA-challenged WT mice exhibited increased HS expression in the lungs along with airway eosinophilia, mucus hypersecretion, peribronchial fibrosis, increased airway epithelial thickness and smooth muscle mass. In OVA-challenged Ndst1-deficient mice, lung eosinophil and macrophage infiltration as well as airway mucus accumulation, peribronchial fibrosis and airway epithelial thickness were significantly lower than in allergen-challenged WT mice along with a trend toward decreased airway smooth muscle mass. Leukocyte and endothelial Ndst 1 deficiency also resulted in significantly decreased expression of IL-13 as well as remodeling-associated mediators such as VEGF, FGF-2 and TGF-β1 in the lung tissue. At a cellular level, exposure to eotaxin-1 failed to induce TGF-β1 expression by Ndst1-deficient eosinophils relative to WT eosinophils. These studies suggest that leukocyte and endothelial Ndst1-modified HS contribute to the development of allergen-induced airway remodeling by promoting recruitment of inflammatory cells as well as regulating expression of pro-remodeling factors such as IL-13, VEGF, TGF-β1 and FGF-2 in the lung.
authors.affiliation: Department of Veterinary & Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA.
authors.forename: Xiao Na
authors.initials: XN
authors.lastname: Ge
authors.affiliation: Department of Veterinary & Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA.
authors.forename: Sung Gil
authors.initials: SG
authors.lastname: Ha
authors.affiliation: Department of Veterinary & Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA.
authors.forename: Amrita
authors.initials: A
authors.lastname: Rao
authors.affiliation: Department of Veterinary & Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA.
authors.forename: Yana G
authors.initials: YG
authors.lastname: Greenberg
authors.affiliation: Department of Veterinary & Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA.
authors.forename: Muaz Nik
authors.initials: MN
authors.lastname: Rushdi
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.affiliation: Department of Veterinary & Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA.
authors.forename: Savita P
authors.initials: SP
authors.lastname: Rao
authors.affiliation: Department of Veterinary & Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA psrao@umn.edu.
authors.forename: P
authors.initials: P
authors.lastname: Sriramarao
mesh_terms: D056151:Airway Remodeling; D000485:Allergens / Q000276:immunology*; D000818:Animals; D042783:Endothelial Cells / Q000737:chemistry* / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D007962:Leukocytes / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism
chemical_list: D000485:Allergens; D006497:Heparan Sulfate; D011509:Proteoglycans
keywords: FGF-2; N-Deacetylase/N-Sulfotransferase-1; TGF-β; allergen-induced airway remodeling; heparan sulfates