KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma.
KIT Inhibition by Imatinib in Patients with Severe Refractory Asthma.
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伊马替尼在严重难治性哮喘患者中抑制试剂盒。
DOI：
10.1056/nejmoa1613125
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发表时间：
2017-05-18
期刊：
影响因子：
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通讯作者：
Israel E
中科院分区：
文献类型：
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作者：
Cahill KN;Katz HR;Cui J;Lai J;Kazani S;Crosby-Thompson A;Garofalo D;Castro M;Jarjour N;DiMango E;Erzurum S;Trevor JL;Shenoy K;Chinchilli VM;Wechsler ME;Laidlaw TM;Boyce JA;Israel E
肥大细胞存在于尽管糖皮质激素治疗但仍患有严重哮喘的患者的气道中;这些细胞与疾病特征相关，包括生活质量差和哮喘控制不足。干细胞因子及其受体KIT是肥大细胞稳态的核心。我们进行了一项原理验证试验，以评估伊马替尼（一种KIT抑制剂）对气道高反应性（重度哮喘的生理标志物）以及对重度哮喘患者气道肥大细胞数量和活化的影响。我们进行了一项随机、双盲、安慰剂对照、为期24周的伊马替尼试验，治疗控制不佳的重度哮喘患者，这些患者尽管接受了最大限度的药物治疗，但仍有气道高反应性。主要终点是气道高反应性的变化，以1秒内用力呼气量减少20%所需的乙酰甲胆碱浓度（PC 20）来衡量。患者还接受了支气管镜检查。在62名接受随机分组的患者中，伊马替尼治疗比安慰剂更大程度地降低气道高反应性。6个月时，伊马替尼组乙酰甲胆碱PC 20增加了1.73±0.60倍剂量的平均值（±SD），而安慰剂组增加了1.07±0.60倍剂量（P = 0.048）。伊马替尼还降低了血清类胰蛋白酶（肥大细胞活化的标志物）的水平，降低程度大于安慰剂（降低2.02±2.32 ng/ml vs.0.56 ±1.39 ng/ml，P = 0.02）。两组的气道肥大细胞计数均下降。肌肉痉挛和低磷血症在伊马替尼组比安慰剂组更常见。在重度哮喘患者中，伊马替尼可降低气道高反应性、肥大细胞计数和类胰蛋白酶释放。这些结果表明，KIT依赖性过程和肥大细胞有助于严重哮喘的病理生物学基础。（由美国国立卫生研究院和其他机构资助; ClinicalTrials.gov编号，NCT 01097694。
Mast cells are present in the airways of patients who have severe asthma despite glucocorticoid treatment; these cells are associated with disease characteristics including poor quality of life and inadequate asthma control. Stem cell factor and its receptor, KIT, are central to mast-cell homeostasis. We conducted a proof-of-principle trial to evaluate the effect of imatinib, a KIT inhibitor, on airway hyper-responsiveness, a physiological marker of severe asthma, as well as on airway mast-cell numbers and activation in patients with severe asthma. We conducted a randomized, double-blind, placebo-controlled, 24-week trial of imatinib in patients with poorly controlled severe asthma who had airway hyperresponsiveness despite receiving maximal medical therapy. The primary end point was the change in airway hyperresponsiveness, measured as the concentration of methacholine required to decrease the forced expiratory volume in 1 second by 20% (PC20). Patients also underwent bronchoscopy. Among the 62 patients who underwent randomization, imatinib treatment reduced airway hyperresponsiveness to a greater extent than did placebo. At 6 months, the methacholine PC20 increased by a mean (±SD) of 1.73±0.60 doubling doses in the imatinib group, as compared with 1.07±0.60 doubling doses in the placebo group (P = 0.048). Imatinib also reduced levels of serum tryptase, a marker of mast-cell activation, to a greater extent than did placebo (decrease of 2.02±2.32 vs. 0.56±1.39 ng per milliliter, P = 0.02). Airway mast-cell counts declined in both groups. Muscle cramps and hypophosphatemia were more common in the imatinib group than in the placebo group. In patients with severe asthma, imatinib decreased airway hyperresponsiveness, mast-cell counts, and tryptase release. These results suggest that KIT-dependent processes and mast cells contribute to the pathobiologic basis of severe asthma. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01097694.)