BACKGROUND The combination of antibacterial and mucolytic actions makes nitric oxide (NO) an attractive dual-action cystic fibrosis (CF) therapeutic. The delivery of any therapeutic agent through pathological mucus is difficult, and the use of inhaled NO gas is inherently limited by toxicity concerns. Herein, we directly compare the ability of NO to eradicate infection and decrease mucus viscoelastic moduli as a function of delivery method (i.e., as a gas or water-soluble chitosan donor). METHODS To compare bactericidal action in tissue, an ex vivo porcine lung model was infected and treated with either gaseous NO or NO-releasing chitosan for 5 h. In vitro Pseudomonas aeruginosa biofilm viability was quantified after NO treatment. Human bronchial epithelial mucus and CF sputum were exposed to NO and their viscoelastic moduli measured with parallel plate macrorheology. RESULTS Larger NO concentrations were achieved in solution when delivered by chitosan relative to gas exposure. The bactericidal action in tissue of the NO-releasing chitosan was greater compared to NO gas in the infected tissue model. Chitosan delivery also resulted in improved antibiofilm action and reduced biofilm viability (2-log) while gaseous delivery had no impact at an equivalent dose (~0.8 µmol/mL). At equivalent NO doses, mucus and sputum rheology were significantly reduced after treatment with NO-releasing chitosan with NO gas having no significant effect. CONCLUSIONS Delivery of NO by chitosan allows for larger in-solution concentrations than achievable via direct gas with superior bactericidal and mucolytic action.

中文翻译：

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使用体外和离体模型通过气体或大分子供体递送的一氧化氮的抗生物膜和粘液溶解作用

背景抗菌和粘液溶解作用的组合使一氧化氮（NO）成为有吸引力的双作用囊性纤维化（CF）治疗剂。通过病理性粘液递送任何治疗剂都是困难的，并且吸入 NO 气体的使用本质上受到毒性问题的限制。在此，我们直接比较了 NO 根除感染和降低粘液粘弹性模量的能力作为递送方法的函数（即，作为气体或水溶性壳聚糖供体）。方法 为了比较组织中的杀菌作用，感染离体猪肺模型并用气态 NO 或释放 NO 的壳聚糖处理 5 小时。体外铜绿假单胞菌生物膜活力在 NO 处理后进行量化。将人支气管上皮粘液和 CF 痰暴露于 NO 中，并用平行板宏观流变学测量它们的粘弹性模量。结果 相对于气体暴露，当由壳聚糖递送时，溶液中的 NO 浓度更高。与感染组织模型中的 NO 气体相比，释放 NO 的壳聚糖在组织中的杀菌作用更大。壳聚糖递送还导致抗生物膜作用的改善和生物膜活力的降低 (2-log)，而气体递送在等效剂量 (~0.8 µmol/mL) 下没有影响。在等量 NO 剂量下，用释放 NO 的壳聚糖处理后，粘液和痰液的流变学显着降低，NO 气体没有显着影响。