Cigarette smoking causes acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction and is associated with delayed mucociliary clearance and chronic bronchitis. Roflumilast is a clinically approved phosphodiesterase 4 inhibitor that improves lung function in patients with chronic bronchitis. We hypothesized that its therapeutic benefit was related in part to activation of CFTR. Primary human bronchial epithelial (HBE) cells, Calu-3, and T84 monolayers were exposed to whole cigarette smoke (WCS) or air with or without roflumilast treatment. CFTRdependent ion transport was measured in modified Ussing chambers. Airway surface liquid (ASL) was determined by confocal microscopy. Intestinal fluid secretion of ligated murine intestine was monitored ex vivo. Roflumilast activated CFTR-dependent anion transport in normal HBE cells with a half maximal effective concentration of 2.9 nM. Roflumilast partially restored CFTR activity in WCS-exposed HBE cells (5.3 6 1.1 mA/cm 2 vs. 1.2 6 0.2 mA/cm 2 [control]; P , 0.05) and was additive with ivacaftor, a specific CFTR potentiator approved for the treatment of CF. Roflumilast improved the depleted ASL depth of HBE monolayers exposed to WCS (9.0 6 3.1 mm vs. 5.6 6 2.0 mm [control]; P , 0.05), achieving 79% of that observed in air controls. CFTR activation by roflumilast also induced CFTR-dependent fluid secretion in murine intestine, increasing the wet:dry ratio and the diameter of ligated murine segments. Roflumilast activates CFTR-mediated anion transport in airway and intestinal epithelia via a cyclic adenosine monophosphate-dependent pathway and partially reverses the deleterious effects of WCS, resulting in augmented ASL depth. Roflumilast may benefit patients with chronic obstructive pulmonary disease with chronic bronchitis by activating CFTR, which may also underlie noninfectious diarrhea caused by roflumilast.

Background Acute pulmonary exacerbations are associated with progressive lung function decline and increased mortality in cystic fibrosis (CF). The role of pulmonary vascular disease in pulmonary exacerbations is unknown. We investigated the association between pulmonary artery enlargement (PA:A>1), a marker of pulmonary vascular disease, and exacerbations. Methods We analyzed clinical, computed tomography (CT), and prospective exacerbation data in a derivation cohort of 74 adult CF patients, measuring the PA:A at the level of the PA bifurcation. We then replicated our findings in a validation cohort of 190 adult CF patients. Patients were separated into groups based on the presence or absence of a PA:A>1 and were followed for 1-year in the derivation cohort and 2-years in the validation cohort. The primary endpoint was developing ≥1 acute pulmonary exacerbation during follow-up. Linear and logistic regression models were used to determine associations between clinical factors, the PA:A ratio, and pulmonary exacerbations. We used Cox regression to determine time to first exacerbation in the validation cohort. Findings We found that PA:A>1 was present in n=37/74 (50%) of the derivation and n=89/190 (47%) of the validation cohort. In the derivation cohort, n=50/74 (68%) had ≥1 exacerbation at 1 year and n=133/190 (70%) in the validation cohort had ≥1 exacerbation after 2 years. PA:A>1 was associated with younger age in both cohorts and with elevated sweat chloride (100.5±10.9 versus 90.4±19.9mmol/L, difference between groups 10.1mmol/L [95%CI 2.5–17.7], P=0.017) in the derivation group. PA:A>1 was associated with exacerbations in the derivation (OR 3.49, 95%CI 1.18–10.3, P=0.023) and validation (OR 2.41, 95%CI 1.06–5.52, P=0.037) cohorts when adjusted for confounders. Time to first exacerbation was shorter in PA:A>1 versus PA:A<1 [HR 1.66 (95%CI 1.18–2.34), P=0.004] in unadjusted analysis, but not when adjusted for sex, BMI, prior exacerbation, positive Pseudomonas status, and FEV1/FVC [HR 1.14 (95%CI 0.80–1.62), P=0.82]). Interpretation PA enlargement is prevalent in adult CF patients and is associated with acute pulmonary exacerbation risk in two well-characterized cohorts. PA:A may be a predictive marker in CF.