Acquired defects in CFTR-dependent β-adrenergic sweat secretion in chronic obstructive pulmonary disease

Abstract

Rationale: Smoking-induced chronic obstructive pulmonary disease (COPD) is associated with acquired systemic cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. Recently, sweat evaporimetry has been shown to efficiently measure β-adrenergic sweat rate and specifically quantify CFTR function in the secretory coil of the sweat gland.

Objectives: To evaluate the presence and severity of systemic CFTR dysfunction in smoking-related lung disease using sweat evaporimetry to determine CFTR-dependent sweat rate.

Methods: We recruited a cohort of patients consisting of healthy never smokers (N = 18), healthy smokers (12), COPD smokers (25), and COPD former smokers (12) and measured β-adrenergic sweat secretion rate with evaporative water loss, sweat chloride, and clinical data (spirometry and symptom questionnaires).

Measurements and main results: β-adrenergic sweat rate was reduced in COPD smokers (41.9 ± 3.4, P < 0.05, ± SEM) and COPD former smokers (39.0 ± 5.4, P < 0.05) compared to healthy controls (53.6 ± 3.4). Similarly, sweat chloride was significantly greater in COPD smokers (32.8 ± 3.3, P < 0.01) and COPD former smokers (37.8 ± 6.0, P < 0.01) vs. healthy controls (19.1 ± 2.5). Univariate analysis revealed a significant association between β-adrenergic sweat rate and female gender (β = 0.26), age (-0.28), FEV1% (0.35), dyspnea (-0.3), and history of smoking (-0.27; each P < 0.05). Stepwise multivariate regression included gender (0.39) and COPD (-0.43) in the final model (R()2 = 0.266, P < 0.0001).

Conclusions: β-adrenergic sweat rate was significantly reduced in COPD patients, regardless of smoking status, reflecting acquired CFTR dysfunction and abnormal gland secretion in the skin that can persist despite smoking cessation. β-adrenergic sweat rate and sweat chloride are associated with COPD severity and clinical symptoms, supporting the hypothesis that CFTR decrements have a causative role in COPD pathogenesis.

Figure 1

Subject disposition.

Figure 2

Systemic CFTR dysfunction in COPD subjects as demonstrated by β-Adrenergic sweat secretion rate. (A) Representative sweat secretion assay tracings of a healthy never smoker (solid) and a COPD patient (dotted). Evaporative water loss is measured continuously following injection of (a¹) atropine, (c) carbachol, (a²) atropine again, and (b) β-adrenergic cocktail stimulus. The stable β-adrenergic stimulated sweat secretion rate is marked with a bar. (B) Summary data plotting maximal β-adrenergic sweat rate for each individual subject. *P < 0.05.

Figure 3

Sweat chloride abnormality in COPD subjects. Quantitative pilocarpine iontophoresis measured concurrently to the β-adrenergic sweat test in each subject. **P < 0.01.

Figure 4

Relationship between sweat chloride and β-adrenergic sweat rate. Sweat chloride (x-axis) and β-adrenergic sweat rate (y-axis) are plotted for each individual subject (A) and by disease group (B). Regression line shown in (B) was statistically significant (R² = 0.933, P < 0.05).

Figure 5

Relationship between sweat tests and CFTR function estimated by nasal potential difference. (A) Based on previously reported values from the literature, sweat chloride and β-adrenergic Sweat Rate are plotted against percent CFTR function as measured by nasal potential difference (NPD). (B) Sweat chloride and evaporimetry data represented as percent normal sweat test from this study for COPD smokers (∇) and COPD former smokers (Δ) are interpolated and plotted on each curve. CF-PI = pancreatic insufficient CF; CF-PS = pancreatic sufficient CF [12,14].