Department of Research, Mount Sinai Medical Center, Miami Beach, Florida, USA.
Respir Res. 2012 Jan 23;13(1):6. doi: 10.1186/1465-9921-13-6.
Previous studies showed that heparin's anti-allergic activity is molecular weight dependent and resides in oligosaccharide fractions of <2500 daltons.
To investigate the structural sequence of heparin's anti-allergic domain, we used nitrous acid depolymerization of porcine heparin to prepare an oligosaccharide, and then fractionated it into disaccharide, tetrasaccharide, hexasaccharide, and octasaccharide fractions. The anti-allergic activity of each oligosaccharide fraction was tested in allergic sheep.
Allergic sheep without (acute responder) and with late airway responses (LAR; dual responder) were challenged with Ascaris suum antigen with and without inhaled oligosaccharide pretreatment and the effects on specific lung resistance and airway hyperresponsiveness (AHR) to carbachol determined. Additional inflammatory cell recruitment studies were performed in immunized ovalbumin-challenged BALB/C mice with and without treatment.
The inhaled tetrasaccharide fraction was the minimal effective chain length to show anti-allergic activity. This fraction showed activity in both groups of sheep; it was also effective in inhibiting LAR and AHR, when administered after the antigen challenge. Tetrasaccharide failed to modify the bronchoconstrictor responses to airway smooth muscle agonists (histamine, carbachol and LTD4), and had no effect on antigen-induced histamine release in bronchoalveolar lavage fluid in sheep. In mice, inhaled tetrasaccharide also attenuated the ovalbumin-induced peribronchial inflammatory response and eosinophil influx in the bronchoalveolar lavage fluid. Chemical analysis identified the active structure to be a pentasulfated tetrasaccharide ([IdoU2S (1→4)GlcNS6S (1→4) IdoU2S (1→4) AMan-6S]) which lacked anti-coagulant activity.
These results demonstrate that heparin tetrasaccharide possesses potent anti-allergic and anti-inflammatory properties, and that the domains responsible for anti-allergic and anti-coagulant activity are distinctly different.
先前的研究表明肝素的抗过敏活性与其分子量有关，存在于分子量<2500 道尔顿的低聚糖片段中。
为了研究肝素抗过敏结构域的序列，我们采用亚硝酸降解猪肝素制备低聚糖，然后将其分为二糖、四糖、六糖和八糖片段。在过敏性绵羊中测试各低聚糖片段的抗过敏活性。
无（急性应答者）和有迟发性气道反应（LAR；双重应答者）的过敏性绵羊在阿苯达唑抗原攻击前和攻击后吸入低聚糖，并测定其对特异性肺阻力和乙酰甲胆碱气道高反应性（AHR）的影响。在卵白蛋白激发的 BALB/C 小鼠中进行了附加的炎症细胞募集研究，这些小鼠分为治疗组和未治疗组。
吸入的四糖片段是显示抗过敏活性的最小有效链长。该片段在两组绵羊中均具有活性；在抗原攻击后给予该片段，还能抑制 LAR 和 AHR。四糖未能修饰对气道平滑肌激动剂（组胺、乙酰甲胆碱和 LTD4）的支气管收缩反应，对绵羊支气管肺泡灌洗液中抗原诱导的组胺释放也无影响。在小鼠中，吸入的四糖也能减轻卵白蛋白诱导的支气管周围炎症反应和支气管肺泡灌洗液中的嗜酸性粒细胞浸润。化学分析确定了具有活性的结构为五硫酸化四糖（[IdoU2S（1→4）GlcNS6S（1→4）IdoU2S（1→4）AMan-6S]），它缺乏抗凝血活性。
这些结果表明肝素四糖具有强大的抗过敏和抗炎特性，并且负责抗过敏和抗凝血活性的结构域明显不同。
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