y HDAC6 depletion improves cystic fibrosis mouse airway responses to bacterial challenge
y HDAC6 depletion improves cystic fibrosis mouse airway responses to bacterial challenge
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DOI：
10.1038/s41598-019-46555-4
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发表时间：
2019-07-16
影响因子：
4.6
通讯作者：
Kelley, Thomas J.
中科院分区：
文献类型：
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作者：
Rosenjack, Julie;Hodges, Craig A.;Kelley, Thomas J.
本研究的假设是，在CF小鼠模型中，Hdac6缺失将使囊性纤维化（CF）对细菌攻击的反应恢复到更多的野生型谱。携带F508del Cftr突变的CF小鼠对将25,000 CFU铜绿假单胞菌嵌入琼脂糖珠以减缓清除的细菌攻击作出反应。与WT小鼠相比，CF小鼠在细菌清除、体重减轻、中性粒细胞募集和MIP-2产生方面对这种挑战的反应明显更积极。CF小鼠中Hdac6表达的缺失（CF/Hdac6）显著改善了这些反应到更高的WT水平。感染后的体重减轻在CF小鼠中最为严重，而在CF/Hdac6小鼠中体重减轻明显。与持续感染的CF小鼠相比，CF/Hdac6小鼠的细菌水平下降速度更快。CF小鼠感染后肺灌洗液中性粒细胞百分比显著升高，但CF/Hdac6小鼠恢复到WT水平。同样，在没有Hdac6表达的情况下，CF Mip-2水平恢复到WT水平。这些数据表明，Hdac6缺失可恢复CF对细菌攻击的wt样谱的反应，并为解决CF气道炎症和感染提供了一种独立于Cftr校正的潜在治疗途径。
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.