Adam Ryan J, Hisert Katherine B, Dodd Jonathan D, Grogan Brenda, Launspach Janice L, Barnes Janel K, Gallagher Charles G, Sieren Jered P, Gross Thomas J, Fischer Anthony J, Cavanaugh Joseph E, Hoffman Eric A, Singh Pradeep K, Welsh Michael J, McKone Edward F, Stoltz David A
Department of Biomedical Engineering.
Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
JCI Insight. 2016 Apr 7;1(4):e86183. doi: 10.1172/jci.insight.86183.
Airflow obstruction is common in cystic fibrosis (CF), yet the underlying pathogenesis remains incompletely understood. People with CF often exhibit airway hyperresponsiveness, CF transmembrane conductance regulator (CFTR) is present in airway smooth muscle (ASM), and ASM from newborn CF pigs has increased contractile tone, suggesting that loss of CFTR causes a primary defect in ASM function. We hypothesized that restoring CFTR activity would decrease smooth muscle tone in people with CF.
To increase or potentiate CFTR function, we administered ivacaftor to 12 adults with CF with the mutation; ivacaftor stimulates G551D-CFTR function. We studied people before and immediately after initiation of ivacaftor (48 hours) to minimize secondary consequences of CFTR restoration. We tested smooth muscle function by investigating spirometry, airway distensibility, and vascular tone.
Ivacaftor rapidly restored CFTR function, indicated by reduced sweat chloride concentration. Airflow obstruction and air trapping also improved. Airway distensibility increased in airways less than 4.5 mm but not in larger-sized airways. To assess smooth muscle function in a tissue outside the lung, we measured vascular pulse wave velocity (PWV) and augmentation index, which both decreased following CFTR potentiation. Finally, change in distensibility of <4.5-mm airways correlated with changes in PWV.
Acute CFTR potentiation provided a unique opportunity to investigate CFTR-dependent mechanisms of CF pathogenesis. The rapid effects of ivacaftor on airway distensibility and vascular tone suggest that CFTR dysfunction may directly cause increased smooth muscle tone in people with CF and that ivacaftor may relax smooth muscle.
This work was funded in part from an unrestricted grant from the Vertex Investigator-Initiated Studies Program.
气流阻塞在囊性纤维化（CF）中很常见，但其潜在发病机制仍未完全明确。CF患者常表现出气道高反应性，气道平滑肌（ASM）中存在CF跨膜传导调节因子（CFTR），新生CF猪的ASM收缩张力增加，这表明CFTR缺失导致ASM功能出现原发性缺陷。我们假设恢复CFTR活性会降低CF患者的平滑肌张力。
为增强或提高CFTR功能，我们对12名携带该突变的成年CF患者给予依伐卡托；依伐卡托可刺激G551D-CFTR功能。我们在开始使用依伐卡托之前及用药后立即（48小时）对患者进行研究，以尽量减少CFTR恢复的继发后果。我们通过研究肺功能、气道扩张性和血管张力来测试平滑肌功能。
依伐卡托迅速恢复了CFTR功能，表现为汗液氯化物浓度降低。气流阻塞和气体潴留也有所改善。直径小于4.5毫米的气道扩张性增加，但较大气道则未增加。为评估肺外组织的平滑肌功能，我们测量了血管脉搏波速度（PWV）和增强指数，CFTR增强后两者均降低。最后，直径<4.5毫米气道扩张性的变化与PWV的变化相关。
急性CFTR增强为研究CF发病机制中CFTR依赖性机制提供了独特机会。依伐卡托对气道扩张性和血管张力的快速作用表明，CFTR功能障碍可能直接导致CF患者平滑肌张力增加，且依伐卡托可能使平滑肌松弛。
本研究部分由Vertex研究者发起研究项目的无限制赠款资助。
