Department of Medicine, University of Alabama at Birmingham, MCLM 706 1918 University Blvd,, Birmingham, AL, USA.
Respir Res. 2014 Feb 11;15(1):18. doi: 10.1186/1465-9921-15-18.
Cigarette smoking causes Chronic Obstructive Pulmonary Disease (COPD), the 3rd leading cause of death in the U.S. CFTR ion transport dysfunction has been implicated in COPD pathogenesis, and is associated with chronic bronchitis. However, susceptibility to smoke induced lung injury is variable and the underlying genetic contributors remain unclear. We hypothesized that presence of CFTR mutation heterozygosity may alter susceptibility to cigarette smoke induced CFTR dysfunction. Consequently, COPD patients with chronic bronchitis may have a higher rate of CFTR mutations compared to the general population.
Primary human bronchial epithelial cells derived from F508del CFTR heterozygotes and mice with (CFTR+/-) and without (CFTR+/+) CFTR heterozygosity were exposed to whole cigarette smoke (WCS); CFTR-dependent ion transport was assessed by Ussing chamber electrophysiology and nasal potential difference measurements, respectively. Caucasians with COPD and chronic bronchitis, age 40 to 80 with FEV1/FVC < 0.70 and FEV1 < 60% predicted, were selected for genetic analysis from participants in the NIH COPD Clinical Research Network's Azithromycin for Prevention of Exacerbations of COPD in comparison to 32,900 Caucasian women who underwent prenatal genetic testing. Genetic analysis involved an allele-specific genotyping of 89 CFTR mutations.
Exposure to WCS caused a pronounced reduction in CFTR activity in both CFTR (+/+) cells and F508del CFTR (+/-) cells; however, neither the degree of decrement (44.7% wild-type vs. 53.5% F508del heterozygous, P = NS) nor the residual CFTR activity were altered by CFTR heterozygosity. Similarly, WCS caused a marked reduction in CFTR activity measured by NPD in both wild type and CFTR heterozygous mice, but the severity of decrement (91.1% wild type vs. 47.7% CF heterozygous, P = NS) and the residual activity were not significantly affected by CFTR genetic status. Five of 127 (3.9%) COPD patients with chronic bronchitis were heterozygous for CFTR mutations which was not significantly different from controls (4.5%) (P = NS).
The magnitude of WCS induced reductions in CFTR activity was not affected by the presence of CFTR mutation heterozygosity. CFTR mutations do not increase the risk of COPD with chronic bronchitis. CFTR dysfunction due to smoking is primarily an acquired phenomenon and is not affected by the presence of congenital CFTR mutations.
吸烟会导致慢性阻塞性肺疾病（COPD），这是美国的第三大死因。CFTR 离子转运功能障碍与 COPD 的发病机制有关，并与慢性支气管炎有关。然而，对烟雾引起的肺损伤的易感性是不同的，潜在的遗传因素仍不清楚。我们假设 CFTR 突变杂合性的存在可能会改变对香烟烟雾引起的 CFTR 功能障碍的易感性。因此，患有慢性支气管炎的 COPD 患者可能比一般人群具有更高的 CFTR 突变率。
从 F508del CFTR 杂合子的原代人支气管上皮细胞和具有（CFTR+/-）和不具有（CFTR+/+）CFTR 杂合子的小鼠中提取，然后用全烟（WCS）进行暴露；通过 Ussing 室电生理学和鼻电位差测量分别评估 CFTR 依赖性离子转运。从 NIH COPD 临床研究网络的阿奇霉素预防 COPD 加重与 32900 名接受产前遗传检测的高加索女性相比，选择年龄在 40 至 80 岁之间、FEV1/FVC<0.70 和 FEV1<60%预测值的 COPD 合并慢性支气管炎患者进行遗传分析。遗传分析包括对 89 种 CFTR 突变的等位基因特异性基因分型。
WCS 暴露导致 CFTR（+/+）细胞和 F508del CFTR（+/−）细胞中的 CFTR 活性明显降低；然而，无论是递减的程度（野生型 44.7% vs. 杂合子 53.5% F508del，P=NS）还是残留的 CFTR 活性都没有因 CFTR 杂合性而改变。同样，WCS 导致通过 NPD 测量的 CFTR 活性在野生型和 CFTR 杂合小鼠中都明显降低，但递减的严重程度（野生型 91.1% vs. CF 杂合子 47.7%，P=NS）和残留活性没有显著受到 CFTR 遗传状态的影响。在 127 名患有慢性支气管炎的 COPD 患者中，有 5 名（3.9%）为 CFTR 突变杂合子，与对照组（4.5%）无显著差异（P=NS）。
WCS 诱导的 CFTR 活性降低的幅度不受 CFTR 突变杂合性的影响。CFTR 突变不会增加患有慢性支气管炎的 COPD 的风险。由于吸烟导致的 CFTR 功能障碍主要是后天现象，不受先天性 CFTR 突变的影响。
