Ivacaftor ameliorates mucus burden, bacterial load, and inflammation in acute but not chronic P. aeruginosa infection in hG551D rats.

IF 5.8 2区 医学 Q1 Medicine Respiratory Research Pub Date : 2024-11-04 DOI:10.1186/s12931-024-03029-0
Johnathan D Keith, Mikayla Murphree-Terry, Gretchen Bollar, Ashley M Oden, Ian H Doty, Susan E Birket
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Abstract

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.

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伊伐卡夫托能减轻 hG551D 大鼠急性铜绿假单胞菌感染时的粘液负担、细菌负荷和炎症,但不能减轻慢性铜绿假单胞菌感染时的粘液负担、细菌负荷和炎症。
背景:新批准的高效调节疗法(HEMT)改变了 CF 患者的生活。虽然这些药物显著改善了肺功能和病情恶化率,但肺部的细菌种群并未根除。持续定植背后的机制尚不完全清楚:我们使用人源化大鼠来评估伊伐卡夫托治疗对感染结果的影响。hG551D大鼠在感染铜绿假单胞菌期间或之前接受伊伐卡夫托治疗。感染反应通过肺部细菌负荷和肺部粘液负荷进行评估:结果:我们发现,使用伊伐卡夫托治疗的hG551D大鼠在感染的急性期肺部细菌数量减少,但在感染的慢性期与药物对照组相比没有差异。同样,气道中的中性粒细胞百分比在急性期也有所减少,但在慢性期则没有减少。总体体重数据表明,使用伊伐卡夫托治疗后,hG551D大鼠在感染过程中的体重恢复情况明显更好。伊伐卡夫托对 G551D 突变的增效作用使短路电流测量结果与 WT 相同,甚至在感染的慢性阶段也是如此。尽管存在持续感染,但使用伊伐卡夫托治疗的 hG551D 大鼠在慢性感染期间出现粘液栓塞的气道数量较少:数据表明,与载体组相比,接受伊伐卡夫托治疗的 hG551D 大鼠在感染期间的疗效更好。尽管感染和炎症持续存在,但大鼠的体重增加、CFTR蛋白功能增强、粘液积聚减少。这些数据表明,在这种大鼠模型中,ivacaftor 可改善对感染的耐受性,而不是根除感染。
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来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
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