Departments of Pediatrics, Case Western Reserve University Cleveland, Ohio, USA.
Sci Rep. 2019 Jul 16;9(1):10282. doi: 10.1038/s41598-019-46555-4.
The hypothesis of this study was that Hdac6 depletion would restore cystic fibrosis (CF) responses to bacterial challenge to more wild type profiles using a CF mouse model. CF mice harboring the F508del Cftr mutation respond to bacterial challenge with 25,000 CFU Pseudomonas aeruginosa embedded into agarose beads to slow clearance. CF mice respond significantly more aggressively to this challenge compared to WT mice with respect to bacterial clearance, weight loss, neutrophil recruitment, and MIP-2 production. Depletion of Hdac6 expression in the CF mice (CF/Hdac6) significantly improves these responses to more WT levels. Weight loss in response to infection is most severe in CF mice and significantly attenuated in CF/Hdac6 mice. Bacterial levels are reduced at a faster rate in CF/Hdac6 mice compared to CF mice where infection persists. Percent neutrophils in lung lavage fluid post-infection are significantly higher in CF mice, but returned to WT levels with CF/Hdac6 mice. Similarly, CF Mip-2 levels are restored to WT levels in the absence of Hdac6 expression. These data demonstrate that Hdac6 depletion restores CF responses to bacterial challenge to WT-like profiles and offer a potential therapeutic avenue for addressing inflammation and infection in CF airways independently of Cftr correction.
本研究的假设是，使用 CF 小鼠模型，HDAC6 耗竭将使囊性纤维化（CF）对细菌挑战的反应恢复为更野生型的表型。携带 F508del Cftr 突变的 CF 小鼠对细菌挑战的反应更为剧烈，用琼脂糖珠嵌入 25000 CFU 铜绿假单胞菌来减缓清除速度。与 WT 小鼠相比，CF 小鼠对这种挑战的反应更为剧烈，表现在细菌清除率、体重减轻、中性粒细胞募集和 MIP-2 产生方面。CF 小鼠中 HDAC6 表达的耗竭（CF/Hdac6）显著改善了这些反应，使其更接近 WT 水平。感染后体重减轻在 CF 小鼠中最为严重，在 CF/Hdac6 小鼠中明显减轻。与 CF 小鼠相比，CF/Hdac6 小鼠中细菌水平的下降速度更快，而 CF 小鼠中的感染持续存在。感染后肺灌洗液中的中性粒细胞百分比在 CF 小鼠中明显升高，但在 CF/Hdac6 小鼠中恢复到 WT 水平。同样，CF Mip-2 水平在没有 HDAC6 表达的情况下也恢复到 WT 水平。这些数据表明，HDAC6 耗竭使 CF 对细菌挑战的反应恢复为 WT 样表型，并为解决 CF 气道中的炎症和感染提供了一种潜在的治疗途径，而无需纠正 Cftr。
