通过体外和离体模型利用气体或大分子供体输送的一氧化氮的抗生物膜和黏液溶解作用。
Antibiofilm and mucolytic action of nitric oxide delivered via gas or macromolecular donor using in vitro and ex vivo models.
机构信息
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Marsico Lung Institute/CF Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
出版信息
J Cyst Fibros. 2020 Nov;19(6):1004-1010. doi: 10.1016/j.jcf.2020.03.004. Epub 2020 Mar 21.
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.
背景
抗菌和黏液溶解作用的结合使一氧化氮（NO）成为一种有吸引力的囊性纤维化（CF）双重作用治疗药物。任何治疗剂通过病理性黏液的输送都很困难，吸入的 NO 气体的使用受到毒性问题的限制。在此，我们直接比较 NO 作为气体或水溶性壳聚糖供体时，作为一种治疗方法消除感染和降低黏液粘弹性模量的能力。
方法
为了比较组织中的杀菌作用，我们使用离体猪肺模型进行了感染，并分别用气态 NO 或释放 NO 的壳聚糖处理 5 小时。NO 处理后，定量测定了体外铜绿假单胞菌生物膜的存活率。将人支气管上皮黏液和 CF 痰液暴露于 NO 下，并使用平行板宏观流变学测量其粘弹性模量。
结果
与气体暴露相比，壳聚糖输送时溶液中可以达到更大的 NO 浓度。在感染组织模型中，释放 NO 的壳聚糖的杀菌作用比 NO 气体更强。壳聚糖输送还导致抗生物膜作用改善，生物膜存活率降低（2 对数），而等量的气体输送则没有影响（~0.8µmol/mL）。在等量的 NO 剂量下，用释放 NO 的壳聚糖处理后，黏液和痰液的流变学显著降低，而 NO 气体则没有显著影响。
结论
壳聚糖输送的 NO 允许在溶液中达到比直接气体更高的浓度，具有更好的杀菌和黏液溶解作用。
Zotero 插件