Loss of cystic fibrosis transmembrane conductance regulator impairs lung endothelial cell barrier function and increases susceptibility to microvascular damage from cigarette smoke.

Abnormal lung microvascular endothelial vascular barrier function may contribute to pulmonary inflammation, such as that occurring during inhalation of cigarette smoke (CS). Cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel expressed in both epithelial and endothelial cells, regulates the organization of tight junctions between epithelial cells and has also been implicated in the transport of sphingosine-1 phosphate (S1P), a vascular barrier-enhancing sphingolipid. Because CS has been shown to affect CFTR function, we hypothesized that CFTR function contributes to lung endothelial cell barrier and that CFTR dysfunction worsens CS-induced injury. CFTR inhibitors GlyH-101 or CFTRinh172 caused a dose-dependent increase in pulmonary or bronchial endothelial monolayer permeability, which peaked after 4 hours. CFTR inhibition was associated with both intercellular gaps and actin stress fiber formation compared with vehicle-treated cells. Increasing endothelial S1P, either by exogenous treatment or by inhibition of its degradation, significantly improved the barrier function in CFTR-inhibited monolayers. Both cultured lung endothelia and the lung microcirculation visualized in vivo with intravital two-photon imaging of transgenic mice deficient in CFTR showed that CFTR dysfunction increased susceptibility to CS-induced permeability. These results suggested that CFTR function might be required for lung endothelial barrier, including adherence junction stability. Loss of CFTR function, especially concomitant to CS exposure, might promote lung inflammation by increasing endothelial cell permeability, which could be ameliorated by S1P.

Improving inpatient cystic fibrosis pulmonary exacerbation care: two success stories.

BACKGROUND: Pulmonary exacerbations (PEx) in cystic fibrosis (CF) are a frequent cause of hospitalisations and lead to long-term decline in pulmonary function. Successful CF inpatient care requires the coordination of multiple providers and complex therapies. Children's Hospital of Wisconsin (CHW) and Children's Healthcare of Atlanta (CHoA) independently identified PEx inpatient care for focused improvements, with emphasis on improving care coordination and patient outcomes. METHODS: Both centres began by forming multidisciplinary workgroups, including patient and family representatives. CHW's specific aim was to eliminate delays in the time to initial intravenous antibiotics. A written handoff tool was developed to allow more efficient ordering. Efforts at CHoA focused on coordination and consistent care delivery. A written schedule and patient incentive programme were devised to ensure proper administration of treatments and promote patient adherence. RESULTS: At CHW, interventions decreased the mean antibiotic order time by 59% with resultant decrease in administration time by 25%. At CHoA, improvements led to a 42% decrease in the proportion of hospitalisations unsuccessful in returning lung function back to within 90% of baseline. CONCLUSIONS: Inpatient CF PEx care is complex and requires multiple competing activities and treatments. Consistent and timely delivery of these treatments is challenging. Our improvements used the skills and insights of providers and patients to improve, standardise and synchronise care, and to develop tools to coordinate hand offs. With these improvements, applicable to hospital treatment of many other conditions, both centres were successfully able to deliver treatments in a more consistent and timely manner with improved outcomes.