依伐卡托改善 hG551D 大鼠急性但非慢性铜绿假单胞菌感染中的黏液负担、细菌负荷和炎症。
Ivacaftor ameliorates mucus burden, bacterial load, and inflammation in acute but not chronic P. aeruginosa infection in hG551D rats.
机构信息
Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, 1720 2nd Ave S, Birmingham, AL, 35294, USA.
Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
出版信息
Respir Res. 2024 Nov 4;25(1):397. doi: 10.1186/s12931-024-03029-0.
BACKGROUND
Newly approved highly effective modulation therapies (HEMT) have been life-changing for people with CF. Although these drugs have resulted in significant improvements in lung function and exacerbation rate, bacterial populations in the lung have not been eradicated. The mechanisms behind the continued colonization are not completely clear.
METHODS
We used a humanized rat to assess the effects of ivacaftor therapy on infection outcomes. Rats harbor an insert expressing humanized CFTR cDNA, including the G551D mutation. hG551D rats were treated with ivacaftor either during or before infection with P. aeruginosa. The response to infection was assessed by bacterial burden in the lung and mucus burden in the lung.
RESULTS
We found that hG551D rats treated with ivacaftor had reduced bacteria present in the lung in the acute phase of the infection but were not different than vehicle control in the chronic phase of the infection. Similarly, the percentage of neutrophils in the airways were reduced at the acute, but not chronic, timepoints. Overall weight data indicated that the hG551D rats had significantly better weight recovery during the course of infection when treated with ivacaftor. Potentiation of the G551D mutation with ivacaftor resultant in short-circuit current measurements equal to WT, even during the chronic phase of the infection. Despite the persistent infection, hG551D rats treated with ivacaftor had fewer airways with mucus plugs during the chronic infection.
CONCLUSIONS
The data indicate that the hG551D rats have better outcomes during infection when treated with ivacaftor compared to the vehicle group. Rats have increased weight gain, increased CFTR protein function, and decreased mucus accumulation, despite the persistence of infection and inflammation. These data suggest that ivacaftor improves tolerance of infection, rather than eradication, in this rat model.
背景
新批准的高效调节疗法（HEMT）改变了 CF 患者的生活。尽管这些药物显著改善了肺功能和恶化率，但肺部的细菌群并未被根除。持续定植的机制尚不完全清楚。
方法
我们使用人源化大鼠评估 ivacaftor 治疗对感染结果的影响。大鼠携带表达人源化 CFTR cDNA 的插入物，包括 G551D 突变。在感染铜绿假单胞菌之前或期间，用 ivacaftor 治疗 hG551D 大鼠。通过肺部细菌负荷和肺部粘液负荷评估对感染的反应。
结果
我们发现，在感染的急性期，用 ivacaftor 治疗的 hG551D 大鼠肺部的细菌数量减少，但在感染的慢性期与载体对照组无差异。同样，气道中的中性粒细胞百分比在急性时减少，但在慢性时没有减少。总体体重数据表明，在感染过程中用 ivacaftor 治疗的 hG551D 大鼠体重恢复明显更好。用 ivacaftor 增强 G551D 突变导致短路电流测量值与 WT 相等，甚至在感染的慢性期也是如此。尽管持续感染，用 ivacaftor 治疗的 hG551D 大鼠在慢性感染期间气道中粘液栓的数量减少。
结论
数据表明，与载体组相比，用 ivacaftor 治疗的 hG551D 大鼠在感染期间的结果更好。尽管存在持续感染和炎症，大鼠的体重增加、CFTR 蛋白功能增加和粘液积聚减少。这些数据表明，在这种大鼠模型中，ivacaftor 改善了对感染的耐受，而不是根除感染。
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