Abstract：
BACKGROUND: Acrolein, an aldehyde in smoke from tobacco products, inhibits CFTR function in vitro. Ivacaftor is an FDA-approved potentiator that improves mutant CFTR function. This human clinical study investigated the relationship between two urinary markers of tobacco smoke exposure - the acrolein metabolite 3-HPMA and the nicotine metabolite NNAL - and sweat chloride response to ivacaftor in the G551D Observational Trial (GOAL).
METHODS: 3-HPMA (low: <50th centile; moderate: 50-75th centile; high: >75th centile) and NNAL (detectable/undetectable) in GOAL samples was quantified with LC-MS/MS. Self-report of tobacco smoke exposure (Y/N) served as a subjective measure. Change in sweat chloride from pre- to 6 months post-ivacaftor treatment (ΔSC) was the primary CFTR-dependent readout.
RESULTS: The sample included 151 individuals, mean age 20.7 (SD 11.4) years, range 6-59 years. Smoke exposure prevalence was 15 % per self-reports but 27 % based on detectable NNAL. 3-HPMA was increased in those reporting tobacco smoke exposure (607 vs 354 ng/ml, p = 0.008), with a higher proportion of smoke-exposed in the high- vs low-acrolein group (31 % vs 9 %, p=0.040). Compared to low-acrolein counterparts, high-acrolein participants experienced less decrease in sweat chloride (-35.2 vs -48.2 mmol/L; p = 0.020) and had higher sweat chloride values (50.6 vs 37.6 mmol/L; p = 0.020) 6 months post-ivacaftor. The odds of ivacaftor-mediated potentiation to near normative CFTR function (defined as SC6mo <40 mmol/L) was more than twice as high in the low-acrolein cohort (OR: 2.51, p = 0.026).
CONCLUSIONS: Increased urinary 3-HPMA, an acrolein metabolite of tobacco smoke, is associated with a diminished sweat chloride response to ivacaftor potentiation of CFTR function.
METHODS: 3-HPMA (low: <50th centile; moderate: 50-75th centile; high: >75th centile) and NNAL (detectable/undetectable) in GOAL samples was quantified with LC-MS/MS. Self-report of tobacco smoke exposure (Y/N) served as a subjective measure. Change in sweat chloride from pre- to 6 months post-ivacaftor treatment (ΔSC) was the primary CFTR-dependent readout.
RESULTS: The sample included 151 individuals, mean age 20.7 (SD 11.4) years, range 6-59 years. Smoke exposure prevalence was 15 % per self-reports but 27 % based on detectable NNAL. 3-HPMA was increased in those reporting tobacco smoke exposure (607 vs 354 ng/ml, p = 0.008), with a higher proportion of smoke-exposed in the high- vs low-acrolein group (31 % vs 9 %, p=0.040). Compared to low-acrolein counterparts, high-acrolein participants experienced less decrease in sweat chloride (-35.2 vs -48.2 mmol/L; p = 0.020) and had higher sweat chloride values (50.6 vs 37.6 mmol/L; p = 0.020) 6 months post-ivacaftor. The odds of ivacaftor-mediated potentiation to near normative CFTR function (defined as SC6mo <40 mmol/L) was more than twice as high in the low-acrolein cohort (OR: 2.51, p = 0.026).
CONCLUSIONS: Increased urinary 3-HPMA, an acrolein metabolite of tobacco smoke, is associated with a diminished sweat chloride response to ivacaftor potentiation of CFTR function.
摘要：
背景：Acrolein，烟草制品烟雾中的醛，体外抑制CFTR功能。Ivacaftor是FDA批准的增强剂，可改善突变型CFTR功能。这项人体临床研究调查了G551D观察试验（GOAL）中烟草烟雾暴露的两种尿液标志物-丙烯醛代谢物3-HPMA和尼古丁代谢物NNAL-与汗液氯化物对ivacaftor的反应之间的关系。
方法：用LC-MS/MS定量GOAL样品中的3-HPMA（低：<50百分位数；中等：50-75百分位数；高：>75百分位数）和NNAL（可检测/不可检测）。烟草烟雾暴露的自我报告（Y/N）是一种主观测量。依伐卡夫治疗前至治疗后6个月的汗液氯化物变化（ΔSC）是主要的CFTR依赖性读数。
结果：样本包括151个人，平均年龄20.7(SD11.4)岁，6-59年。每个自我报告的烟雾暴露患病率为15％，但基于可检测的NNAL为27％。3-HPMA在报告烟草烟雾暴露的人群中增加(607比354纳克/毫升，p=0.008),高丙烯醛与低丙烯醛组的烟雾暴露比例较高(31%与9%，p=0.040)。与低丙烯醛对应物相比，高丙烯醛组参与者在使用ivacaftor后6个月的汗液氯化物下降较少(-35.2对-48.2mmol/L;p=0.020),汗液氯化物值更高(50.6对37.6mmol/L;p=0.020).在低丙烯醛队列中，ivacaftor介导的增强接近标准CFTR功能（定义为SC6mo<40mmol/L）的几率是其两倍以上（OR：2.51，p=0.026）。
结论：增加尿3-HPMA，一种烟草烟雾的丙烯醛代谢产物,与汗液氯化物对ivacaftor增强CFTR功能的反应减弱有关。
方法：用LC-MS/MS定量GOAL样品中的3-HPMA（低：<50百分位数；中等：50-75百分位数；高：>75百分位数）和NNAL（可检测/不可检测）。烟草烟雾暴露的自我报告（Y/N）是一种主观测量。依伐卡夫治疗前至治疗后6个月的汗液氯化物变化（ΔSC）是主要的CFTR依赖性读数。
结果：样本包括151个人，平均年龄20.7(SD11.4)岁，6-59年。每个自我报告的烟雾暴露患病率为15％，但基于可检测的NNAL为27％。3-HPMA在报告烟草烟雾暴露的人群中增加(607比354纳克/毫升，p=0.008),高丙烯醛与低丙烯醛组的烟雾暴露比例较高(31%与9%，p=0.040)。与低丙烯醛对应物相比，高丙烯醛组参与者在使用ivacaftor后6个月的汗液氯化物下降较少(-35.2对-48.2mmol/L;p=0.020),汗液氯化物值更高(50.6对37.6mmol/L;p=0.020).在低丙烯醛队列中，ivacaftor介导的增强接近标准CFTR功能（定义为SC6mo<40mmol/L）的几率是其两倍以上（OR：2.51，p=0.026）。
结论：增加尿3-HPMA，一种烟草烟雾的丙烯醛代谢产物,与汗液氯化物对ivacaftor增强CFTR功能的反应减弱有关。
