PDF(Pubmed)
Abstract：
Inflammation is a key driver in the pathogenesis of cystic fibrosis (CF). We assessed the effectiveness of elexacaftor/tezacaftor/ivacaftor (ETI) therapy on downregulating systemic and immune cell-derived inflammatory cytokines. We also monitored the impact of ETI therapy on clinical outcome. Adults with CF, heterozygous for F508del (n = 19), were assessed at baseline, one month and three months following ETI therapy, and clinical outcomes were measured, including sweat chloride, lung function, weight, neutrophil count and C-reactive protein (CRP). Cytokine quantifications were measured in serum and following stimulation of peripheral blood mononuclear cells (PBMCs) with lipopolysaccharide (LPS) and adenosine triphosphate and analysed using LEGEND plex™ Human Inflammation Panel 1 by flow cytometry (n = 19). ASC specks were measured in serum and caspase-1 activity and mRNA levels determined from stimulated PBMCs were determined. Patients remained stable over the study period. ETI therapy resulted in decreased sweat chloride concentrations (p < 0.0001), CRP (p = 0.0112) and neutrophil count (p = 0.0216) and increased percent predicted forced expiratory volume (ppFEV1) (p = 0.0399) from baseline to three months, alongside a trend increase in weight. Three months of ETI significantly decreased IL-18 (p< 0.0011, p < 0.0001), IL-1β (p<0.0013, p = 0.0476), IL-6 (p = 0.0109, p = 0.0216) and TNF (p = 0.0028, p = 0.0033) levels in CF serum and following PBMCs stimulation respectively. The corresponding mRNA levels were also found to be reduced in stimulated PBMCs, as well as reduced ASC specks and caspase-1 levels, indicative of NLRP3-mediated production of pro-inflammatory cytokines, IL-1β and IL-18. While ETI therapy is highly effective at reducing sweat chloride and improving lung function, it also displays potent anti-inflammatory properties, which are likely to contribute to improved long-term clinical outcomes.
摘要：
炎症是囊性纤维化（CF）发病机理的关键驱动因素。我们评估了elexacaftor/tezacaftor/ivacaftor（ETI）治疗对下调全身和免疫细胞衍生的炎性细胞因子的有效性。我们还监测了ETI治疗对临床结果的影响。成人CF，F508del杂合(n=19)，在基线评估，ETI治疗后一个月和三个月，并测量临床结果，包括汗液氯化物,肺功能,体重,中性粒细胞计数和C反应蛋白（CRP）。在血清中以及用脂多糖(LPS)和三磷酸腺苷刺激外周血单核细胞(PBMC)后测量细胞因子定量,并使用LEGENDplex™人炎症组1通过流式细胞术分析(n=19)。在血清中测量ASC斑点,并测定半胱天冬酶-1活性和从刺激的PBMC测定的mRNA水平。患者在研究期间保持稳定。ETI治疗导致汗液氯化物浓度降低（p<0.0001），CRP（p=0.0112）和中性粒细胞计数（p=0.0216）以及从基线到三个月的预测用力呼气量（ppFEV1）（p=0.0399）增加的百分比，随着体重的增加。三个月的ETI显著降低IL-18(p<0.0011,p<0.0001),IL-1β（p<0.0013，p=0.0476），CF血清和PBMC刺激后的IL-6(p=0.0109,p=0.0216)和TNF(p=0.0028,p=0.0033)水平分别。在受刺激的PBMC中也发现相应的mRNA水平降低，以及减少ASC斑点和caspase-1水平，指示NLRP3介导的促炎细胞因子的产生，IL-1β和IL-18。虽然ETI治疗在减少汗液氯化物和改善肺功能方面非常有效，它还显示出有效的抗炎特性，这可能有助于改善长期临床结局。
