Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain.
Instituto de Agrobiotecnología, CSIC-Universidad Pública Navarra-Gobierno Navarra, Mutilva, Spain.
Sci Rep. 2017 Oct 16;7(1):12860. doi: 10.1038/s41598-017-13034-7.
The respiratory pathogen nontypeable Haemophilus influenzae (NTHi) is an important cause of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) that requires efficient treatments. A previous screening for host genes differentially expressed upon NTHi infection identified sirtuin-1, which encodes a NAD-dependent deacetylase protective against emphysema and is activated by resveratrol. This polyphenol concomitantly reduces NTHi viability, therefore highlighting its therapeutic potential against NTHi infection at the COPD airway. In this study, resveratrol antimicrobial effect on NTHi was shown to be bacteriostatic and did not induce resistance development in vitro. Analysis of modulatory properties on the NTHi-host airway epithelial interplay showed that resveratrol modulates bacterial invasion but not subcellular location, reduces inflammation without targeting phosphodiesterase 4B gene expression, and dampens β defensin-2 gene expression in infected cells. Moreover, resveratrol therapeutics against NTHi was evaluated in vivo on mouse respiratory and zebrafish septicemia infection model systems, showing to decrease NTHi viability in a dose-dependent manner and reduce airway inflammation upon infection, and to have a significant bacterial clearing effect without signs of host toxicity, respectively. This study presents resveratrol as a therapeutic of particular translational significance due to the attractiveness of targeting both infection and overactive inflammation at the COPD airway.
呼吸道病原体流感嗜血杆菌（NTHi）是慢性阻塞性肺疾病（COPD）急性加重（AECOPD）的重要病因，需要有效的治疗方法。先前的研究筛选出了在 NTHi 感染后差异表达的宿主基因，其中包括编码 NAD 依赖性脱乙酰酶的 Sirtuin-1，这种酶可以预防肺气肿，并且可以被白藜芦醇激活。这种多酚同时降低了 NTHi 的活力，因此突出了其在 COPD 气道中针对 NTHi 感染的治疗潜力。在这项研究中，白藜芦醇对 NTHi 的抗菌作用表现为抑菌作用，并且不会在体外诱导耐药性的发展。对 NTHi-宿主气道上皮相互作用的调节特性的分析表明，白藜芦醇可以调节细菌侵袭，但不会改变亚细胞定位，减少炎症而不针对磷酸二酯酶 4B 基因表达，并且可以抑制感染细胞中 β 防御素-2 基因的表达。此外，在小鼠呼吸道和斑马鱼败血症感染模型系统中评估了白藜芦醇针对 NTHi 的治疗效果，结果表明它可以剂量依赖性地降低 NTHi 的活力，并减轻感染后的气道炎症，并且具有显著的清除细菌作用，而没有宿主毒性的迹象。这项研究表明，白藜芦醇具有特殊的转化意义，因为它可以靶向 COPD 气道中的感染和过度炎症。
