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* Department of Veterinary and Biomedical Sciences and Department of Medicine, University of Minnesota, St. Paul, MN 55108;
Department of Medicine, University of California, San Diego and Veterans Affairs San Diego Healthcare System, La Jolla, CA 92093; and
Department of Medicine, University of California, San Diego, La Jolla, CA 92093
The effect of targeted inactivation of the gene encoding N-deacetylase/N-sulfotransferase-1 (Ndst1), a key enzyme involved in the biosynthesis of heparan sulfate (HS) chains, on the inflammatory response associated with allergic inflammation in a murine model of OVA-induced acute airway inflammation was investigated. OVA-exposed Ndst1f/fTekCre+ (mutant) mice deficient in endothelial and leukocyte Ndst1 demonstrated significantly decreased allergen-induced airway hyperresponsiveness and inflammation characterized by a significant reduction in airway recruitment of inflammatory cells (eosinophils, macrophages, neutrophils, and lymphocytes), diminished IL-5, IL-2, TGF-β1, and eotaxin levels, as well as decreased expression of TGF-β1 and the angiogenic protein FIZZ1 (found in inflammatory zone 1) in lung tissue compared with OVA-exposed Ndst1f/fTekCre– wild-type littermates. Furthermore, murine eosinophils demonstrated significantly decreased rolling on lung endothelial cells (ECs) from mutant mice compared with wild-type ECs under conditions of flow in vitro. Treatment of wild-type ECs, but not eosinophils, with anti-HS Abs significantly inhibited eosinophil rolling, mimicking that observed with Ndst1-deficient ECs. In vivo, trafficking of circulating leukocytes in lung microvessels of allergen-challenged Ndst1-deficient mice was significantly lower than that observed in corresponding WT littermates. Endothelial-expressed HS plays an important role in allergic airway inflammation through the regulation of recruitment of inflammatory cells to the airways by mediating interaction of leukocytes with the vascular endothelium. Furthermore, HS may also participate by sequestering and modulating the activity of allergic asthma-relevant mediators such as IL-5, IL-2, and TGF-β1.
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1 This work was supported by National Institutes of Health grants U19-AI70535, HL0793041, AI35796 (to P.S.), and HL57345 (to J.D.E.), and a Career Development Award from the Department of Veterans Affairs (to M.M.F.).
2 Address correspondence and reprint requests to Dr. P. Srirama Rao, Department of Veterinary and Biomedical Sciences, University of Minnesota, 445 VMC, 1365 Gortner Avenue, St. Paul, MN 55108. E-mail address: psrao{at}umn.edu
3 Abbreviations used in this paper: HS, heparan sulfate; GAG, glycosaminoglycan; HSPG, heparan sulfate proteoglycan; ECM, extracellular matrix; Ndst1, N-deacetylase/N-sulfotransferase-1; EC, endothelial cells; AHR, airway hyperresponsiveness; WT, wild type; MCh, methacholine; BALF, bronchoalveolar lavage fluid; MBP, major basic protein; FIZZ1, found in inflammatory zone 1; MLEC, murine lung endothelial cells; IVM, intravital microscopy.
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