The Stanley S. Scott Cancer Center, LSU Health Sciences Center-New Orleans, 1700 Tulane Ave, New Orleans, LA, 70112, USA.
The Department of Microbiology and Immunology, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
J Transl Med. 2018 Sep 1;16(1):243. doi: 10.1186/s12967-018-1621-5.
The efficacy of heparins and low-MW-heparins (LMWH) against human asthma has been known for decades. However, the clinical utility of these compounds has been hampered by their anticoagulant properties. Much effort has been put into harnessing the anti-inflammatory properties of LMWH but none have been used as therapy for asthma. Sulfated-non-anticoagulant heparin (S-NACH) is an ultra-LMWH with no systemic anticoagulant effects.
The present study explored the potential of S-NACH in blocking allergic asthma and examined the potential mechanism by which it exerts its effects.
Acute and chronic ovalbumin-based mouse models of asthma, splenocytes, and a lung epithelial cell line were used. Mice were challenged with aerosolized ovalbumin and administered S-NACH or saline 30 min after each ovalbumin challenge.
Sulfated-non-anticoagulant heparin administration in mice promoted a robust reduction in airway eosinophilia, mucus production, and airway hyperresponsiveness even after chronic repeated challenges with ovalbumin. Such effects were linked to suppression of Th2 cytokines IL-4/IL-5/IL-13/GM-CSF and ovalbumin-specific IgE without any effect on IFN-γ. S-NACH also reduced lung fibrosis in mice that were chronically-exposed to ovalbumin. These protective effects of S-NACH may be attributed to modulation of the IL-4/JAK1 signal transduction pathway through an inhibition of STAT6 phosphorylation and a subsequent inhibition of GATA-3 and inducible NO synthase expression. The effect of the drug on STAT6 phosphorylation coincided with a reduction in JAK1 phosphorylation upon IL-4 treatment. The protective effects of S-NACH treatment was associated with reduction of the basal expression of the two isoforms of arginase ARG1 and ARG2 in lung epithelial cells.
Our study demonstrates that S-NACH constitutes an opportunity to benefit from the well-known anti-asthma properties of heparins/LMWH while bypassing the risk of bleeding. Our results show, for the first time, that such anti-asthma effects may be associated with reduction of the IL-4/JAK1/STAT6 pathway.
几十年来，肝素和低分子量肝素（LMWH）对人类哮喘的疗效已为人所知。然而，由于其抗凝特性，这些化合物的临床应用受到了阻碍。人们已经付出了很大的努力来利用 LMWH 的抗炎特性，但没有一种被用作哮喘的治疗方法。硫酸化非抗凝肝素（S-NACH）是一种超低分子量肝素，没有全身抗凝作用。
本研究探讨了 S-NACH 阻断变应性哮喘的潜力，并研究了其发挥作用的潜在机制。
使用急性和慢性卵清蛋白诱导的小鼠哮喘模型、脾细胞和肺上皮细胞系。在每次卵清蛋白激发后 30 分钟，用 S-NACH 或生理盐水处理小鼠。
在卵清蛋白反复激发的慢性模型中，S-NACH 的给药可显著减少气道嗜酸性粒细胞增多、粘液产生和气道高反应性。这种作用与 Th2 细胞因子 IL-4/IL-5/IL-13/GM-CSF 和卵清蛋白特异性 IgE 的抑制有关，而对 IFN-γ没有影响。S-NACH 还可减少慢性暴露于卵清蛋白的小鼠的肺纤维化。S-NACH 的这些保护作用可能归因于通过抑制 STAT6 磷酸化及其随后抑制 GATA-3 和诱导型一氧化氮合酶的表达来调节 IL-4/JAK1 信号转导通路。药物对 STAT6 磷酸化的影响与 IL-4 处理时 JAK1 磷酸化的减少相吻合。S-NACH 治疗的保护作用与肺上皮细胞中两种精氨酸酶 ARG1 和 ARG2 同工型的基础表达减少有关。
本研究表明，S-NACH 为利用肝素/LMWH 众所周知的抗哮喘特性提供了机会，同时避免了出血的风险。我们的研究结果首次表明，这种抗哮喘作用可能与减少 IL-4/JAK1/STAT6 通路有关。
