Department of Research, Mount Sinai Medical Center, 4300 Alton Rd., Miami Beach, FL 33140, USA.
Pulm Pharmacol Ther. 2013 Apr;26(2):180-8. doi: 10.1016/j.pupt.2012.10.004. Epub 2012 Oct 22.
We have shown that inhaled heparin (hep) oligosaccharides attenuate allergic airway responses in sheep and that this anti-allergic activity resides in a tetrasaccharide sequence. Here we determined: (a) the anti-allergic activity of oral and intravenous hep-tetrasaccharide on allergic airway responses in the sheep model of asthma; and (b) the role of N-sulfation in mediating this anti-allergic activity. Ascaris suum-induced early (EAR) and Late (LAR) airway responses and airway hyperresponsiveness (AHR) to carbachol were measured in allergic sheep without and after treatment with different doses of oral or intravenous hep-tetrasaccharide. At doses of 0.06 mg/kg, 0.125 mg/kg, and 0.25 mg/kg, oral hep-tetrasaccharide caused a dose-dependent inhibition of EAR and LAR. Post-antigen AHR was also inhibited dose dependently. The same doses of intravenous hep-tetrasaccharide yielded comparable inhibition of EAR, LAR and AHR, confirming that orally delivered hep-tetrasaccharide has good bioavailability. The protection by hep-tetrasaccharide on EAR and LAR was dependent on N-sulfation, as N-desulfated/N-acetylated tetrasaccharide had a markedly reduced effect. However, inhibition of the post-antigen AHR was independent of N-sulfation. These results demonstrate that orally administered hep-tetrasaccharide inhibits allergic airway responses in the sheep model of asthma. Hep-tetrasaccharide has good oral bioavailability and its anti-allergic activity is critically dependent on N-sulfation of the glucosamine ring.
我们已经表明，吸入肝素（hep）寡糖可减轻绵羊的过敏性气道反应，并且这种抗过敏活性存在于四糖序列中。在这里，我们确定了：（a）口服和静脉注射 hep-四糖对哮喘绵羊模型中过敏性气道反应的抗过敏活性；和（b）N-硫酸化在介导这种抗过敏活性中的作用。在没有和在用不同剂量的口服或静脉注射 hep-四糖治疗后，测量了绵羊中由蛔虫诱导的早期（EAR）和晚期（LAR）气道反应以及对卡巴胆碱的气道高反应性（AHR）。在 0.06mg/kg、0.125mg/kg 和 0.25mg/kg 的剂量下，口服 hep-四糖可剂量依赖性地抑制 EAR 和 LAR。抗原后 AHR 也呈剂量依赖性抑制。相同剂量的静脉注射 hep-四糖对 EAR、LAR 和 AHR 产生类似的抑制作用，证实口服给予的 hep-四糖具有良好的生物利用度。hep-四糖对 EAR 和 LAR 的保护作用依赖于 N-硫酸化，因为 N-去硫酸化/N-乙酰化四糖的作用明显降低。然而，抗原后 AHR 的抑制作用与 N-硫酸化无关。这些结果表明，口服给予的 hep-四糖可抑制哮喘绵羊模型中的过敏性气道反应。hep-四糖具有良好的口服生物利用度，其抗过敏活性严重依赖于氨基葡萄糖环的 N-硫酸化。
