Elexacaftor/tezacaftor/ivacaftor corrects monocyte microbicidal deficiency in cystic fibrosis.
Elexacaftor/tezacaftor/ivacaftor corrects monocyte microbicidal deficiency in cystic fibrosis.
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DOI：
10.1183/13993003.00725-2022
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发表时间：
2023-04
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影响因子：
--
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中科院分区：
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囊性纤维化（CF）是由CF跨膜传导调节因子（CFTR）突变引起的，其特征在于慢性细菌性肺部感染和炎症。在CF中，单核细胞和单核细胞衍生的巨噬细胞显示出对相关肺部病原体（包括铜绿假单胞菌）的吞噬作用和抗微生物活性缺陷。因此，我们解决了CFTR三重调节剂疗法（依拉卡托/替扎卡托/依伐卡托（ETI））对CF单核细胞针对铜绿假单胞菌的活性的影响。在ETI治疗前和治疗后1个月和6个月，从血液中分离CF（PWCF）患者的单核细胞，并感染铜绿假单胞菌，以评估吞噬活性和细胞内细菌杀伤。氧化爆发和白细胞介素-6分泌也进行了测定。还包括来自健康对照的单核细胞。临床参数的纵向分析证实了ETI对肺功能和肺微生物学的改善。CF单核细胞的吞噬和杀微生物缺陷也显著改善，尽管不是完全改善。此外，我们测量了治疗前CF单核细胞中旺盛的氧化爆发，ETI显著降低了氧化爆发。这导致活性氧依赖性杀菌活性的改善。与治疗前相比，对细菌刺激的炎症反应也降低了。在现实生活环境中，除了临床恢复外，ETI治疗的PWCF显示单核细胞对铜绿假单胞菌的活性显著改善，这可能有助于ETI对肺部疾病的总体影响。这也表明CF单核细胞功能障碍可能特异性靶向改善CF中的肺功能。在患有囊性纤维化的人中，elexacaftor/tezacaftor/ivacaftor通过降低其旺盛的氧化爆发来改善单核细胞对铜绿假单胞菌的抗微生物活性，从而有助于改善肺部疾病http://bit.ly/3hL2Z11
Cystic fibrosis (CF), which is caused by mutations in the CF transmembrane conductance regulator (CFTR), is characterised by chronic bacterial lung infection and inflammation. In CF, monocytes and monocyte-derived macrophages have been shown to display defective phagocytosis and antimicrobial activity against relevant lung pathogens, including Pseudomonas aeruginosa. Thus, we addressed the effect of CFTR triple modulator therapy (elexacaftor/tezacaftor/ivacaftor (ETI)) on the activity of CF monocytes against P. aeruginosa. Monocytes from people with CF (PWCF) before and after 1 and 6 months of ETI therapy were isolated from blood and infected with P. aeruginosa to assess phagocytic activity and intracellular bacterial killing. The oxidative burst and interleukin-6 secretion were also determined. Monocytes from healthy controls were also included. Longitudinal analysis of the clinical parameters confirmed an improvement of lung function and lung microbiology by ETI. Both the phagocytic and microbicidal deficiencies of CF monocytes also improved significantly, although not completely. Furthermore, we measured an exuberant oxidative burst in CF monocytes before therapy, which was reduced considerably by ETI. This led to an improvement of reactive oxygen species-dependent bactericidal activity. Inflammatory response to bacterial stimuli was also lowered compared with pre-therapy. PWCF on ETI therapy, in a real-life setting, in addition to clinical recovery, showed significant improvement in monocyte activity against P. aeruginosa, which may have contributed to the overall effect of ETI on pulmonary disease. This also suggests that CF monocyte dysfunctions may be specifically targeted to ameliorate lung function in CF. In people with cystic fibrosis, elexacaftor/tezacaftor/ivacaftor ameliorates the antimicrobial activity of monocytes against Pseudomonas aeruginosa by lowering their exuberant oxidative burst, thus contributing to the improvement of lung disease http://bit.ly/3hL2Z11
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影响因子：
3.7
作者：
Cigana C;Curcurù L;Leone MR;Ieranò T;Lorè NI;Bianconi I;Silipo A;Cozzolino F;Lanzetta R;Molinaro A;Bernardini ML;Bragonzi A
通讯作者：
Bragonzi A
DOI：
10.1164/rccm.202106-1426oc
发表时间：
2022-04-01
影响因子：
24.7
作者：
Gabillard-Lefort, Claudie;Casey, Michelle;Reeves, Emer P.
通讯作者：
Reeves, Emer P.
影响因子：
16.6
作者：
Hey J;Paulsen M;Toth R;Weichenhan D;Butz S;Schatterny J;Liebers R;Lutsik P;Plass C;Mall MA
通讯作者：
Mall MA
影响因子：
3.7
作者：
Cifani N;Pompili B;Anile M;Patella M;Diso D;Venuta F;Cimino G;Quattrucci S;Di Domenico EG;Ascenzioni F;Del Porto P
通讯作者：
Del Porto P
影响因子：
4.6
作者：
Brunel, Shan F.;Willment, Janet A.;Warris, Adilia
通讯作者：
Warris, Adilia