Cystic fibrosis (CF) lung disease is marked by high concentrations of neutrophil elastase (NE) and DNA polymers; both factors contribute to airway disease. Although inhaled recombinant human dornase alfa reduces the frequency of CF pulmonary exacerbations, it also increases free NE activity in the sputum. There are no approved anti-NE therapies for patients with CF. We investigated whether synthetic, low–molecular weight polysulfated hyaluronan GlycoMira-1111 (GM-1111) would be effective as an anti-NE drug using ex vivo CF sputum. Anti-NE activity of GM-1111 was tested in CF sputum in the presence or absence of dornase alfa and/or hypertonic saline using a spectrophotometric assay specific for human NE and was compared with unfractionated heparin. We tested whether GM-1111 disaggregated DNA from CF sputum (using gel electrophoresis analysis) or modified CF sputum viscoelastic properties (using a dynamic rheometer). GM-1111 and unfractionated heparin had near equivalent anti-NE activity in CF sputum in the presence of dornase alfa. Both GM-1111 and unfractionated heparin retained anti-NE activity in hypertonic saline but with decreased activity. GM-1111 increased the release of soluble DNA in CF sputum, resulting in improved depolymerization efficacy of dornase alfa. GM-1111 decreased CF sputum elasticity. GM-1111 inhibited NE activity, enhanced DNA depolymerization by deoxyribonuclease, and decreased viscoelastic properties of CF sputum, similar to effects reported previously for unfractionated heparin. Unlike heparins, GM-1111 is synthetic, with minimal anticoagulant activity, and is not derived from animal products. These key attributes provide advantages over unfractionated heparin as a potential therapeutic for CF.

囊性纤维化 (CF) 肺病的特征是高浓度的中性粒细胞弹性蛋白酶 (NE) 和 DNA 聚合物；这两个因素都会导致气道疾病。尽管吸入重组人多核糖核酸酶 alfa 可降低 CF 肺部恶化的频率，但它也增加了痰液中游离 NE 的活性。目前尚无批准用于 CF 患者的抗 NE 疗法。我们研究了合成的低分子量多硫酸化透明质酸 GlycoMira-1111 (GM-1111) 在体外作为抗 NE 药物是否有效CF痰。GM-1111 的抗 NE 活性在 CF 痰液中使用人类 NE 特异性分光光度测定法在存在或不存在阿尔法酶和/或高渗盐水的情况下进行测试，并与未分级肝素进行比较。我们测试了 GM-1111 是否从 CF 痰液中分解 DNA（使用凝胶电泳分析）或改良的 CF 痰液粘弹性特性（使用动态流变仪）。GM-1111 和普通肝素在 Dornase alfa 存在的情况下在 CF 痰中具有几乎相同的抗 NE 活性。GM-1111 和普通肝素在高渗盐水中都保留了抗 NE 活性，但活性降低。GM-1111增加了CF痰中可溶性DNA的释放，从而提高了dornase alfa的解聚功效。GM-1111 降低 CF 痰弹性。GM-1111 抑制 NE 活性，脱氧核糖核酸酶增强 DNA 解聚，并降低 CF 痰的粘弹性，类似于先前报道的普通肝素的效果。与肝素不同，GM-1111 是合成的，抗凝活性最低，并非来源于动物产品。这些关键属性提供了优于普通肝素作为 CF 潜在治疗剂的优势。