Zuberi Riaz I, Ge Xiao Na, Jiang Shuxia, Bahaie Nooshin S, Kang Bit Na, Hosseinkhani Reza M, Frenzel Elizabeth M, Fuster Mark M, Esko Jeffrey D, Rao Savita P, Sriramarao P
Department of Veterinary and Biomedical Sciences, University of Minnesota, St Paul, MN 55108, USA.
J Immunol. 2009 Sep 15;183(6):3971-9. doi: 10.4049/jimmunol.0901604. Epub 2009 Aug 26.
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 Ndst1(f/f)TekCre(+) (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-beta1, and eotaxin levels, as well as decreased expression of TGF-beta1 and the angiogenic protein FIZZ1 (found in inflammatory zone 1) in lung tissue compared with OVA-exposed Ndst1(f/f)TekCre(-) 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-beta1.
研究了编码N-脱乙酰酶/N-磺基转移酶-1（Ndst1）的基因靶向失活对卵清蛋白（OVA）诱导的急性气道炎症小鼠模型中与过敏性炎症相关的炎症反应的影响。缺乏内皮细胞和白细胞Ndst1的OVA暴露的Ndst1（f/f）TekCre（+）（突变）小鼠表现出变应原诱导的气道高反应性和炎症显著降低，其特征为炎症细胞（嗜酸性粒细胞、巨噬细胞、中性粒细胞和淋巴细胞）向气道募集显著减少，IL-5、IL-2、TGF-β1和嗜酸性粒细胞趋化因子水平降低，与OVA暴露的Ndst1（f/f）TekCre（-）野生型同窝小鼠相比，肺组织中TGF-β1和血管生成蛋白FIZZ1（在炎症区域1中发现）的表达也降低。此外，在体外流动条件下，与野生型内皮细胞相比，来自突变小鼠的鼠嗜酸性粒细胞在肺内皮细胞（ECs）上的滚动显著减少。用抗HS抗体处理野生型ECs而非嗜酸性粒细胞，可显著抑制嗜酸性粒细胞滚动，这与Ndst1缺陷型ECs中观察到的情况相似。在体内，变应原攻击的Ndst1缺陷小鼠肺微血管中循环白细胞的运输显著低于相应野生型同窝小鼠。内皮细胞表达的HS通过介导白细胞与血管内皮细胞的相互作用来调节炎症细胞向气道的募集，从而在过敏性气道炎症中发挥重要作用。此外，HS还可能通过隔离和调节与过敏性哮喘相关的介质如IL-5、IL-2和TGF-β1的活性来参与其中。
