Mucociliary Clearance as an Outcome Measure for Cystic Fibrosis Clinical Research

Abstract

Current concepts of cystic fibrosis (CF) pathophysiology link ion transport abnormalities to reduced airway surface liquid (ASL) hydration and impaired mucus clearance. It is likely that correction of the defects that cause ASL dehydration will prevent degradation of mucus clearance, thereby preventing the initiation and/or progression of CF lung disease. A number of novel therapeutic agents aimed at the earliest steps in disease pathogenesis are now under development for the treatment of CF lung disease. Consequently, there is a tremendous need to develop methods that directly assess the effects of these agents on the underlying pathophysiologic process in the target organ. The measurement of mucociliary clearance (MCC) is a highly biologically relevant outcome, but one that is in need of further development. Here, we describe important methodologic aspects of MCC measurement and issues that have limited its use as an outcome measure in the past. Furthermore, we outline the steps that are being carried out now, and will be carried out in the future, to improve the performance of these studies in clinical trials. A systematic approach to optimizing and standardizing the measurement of MCC should greatly advance our ability to assess novel therapies at a relatively early stage of drug development. The resulting data may then be used to select those candidates that should be rapidly advanced into larger clinical trials.

Histone deacetylase 6–mediated selective autophagy regulates COPD-associated cilia dysfunction

“…MCC acts as a lung defense mechanism against inhaled particles and pathogens. Methodology to determine MCC in humans may represent an important clinical tool to assess airway function in diseases such as COPD or cystic fibrosis (77). In order to test our hypotheses that autophagy plays a maladaptive role in cilia homeostasis, we implemented a physiological model of airway MCC.…”

Continuous mucociliary transport by primary human airway epithelial cells in vitro

“…Thus the ideal system for studying MCC would allow study of all three components, as in a whole animal model; however, studying MCC in vivo is challenging for several reasons. For example, studies of MCC in humans typically measure the disappearance of a radioactive tracer from the lungs over time (8). While these studies are invaluable to our understanding of MCC, due to the use of radioactivity, the need for specialized equipment, and the expense of performing large scale human studies, this approach is not feasible for routine laboratory investigations or high-throughput screening.…”

“…Impaired MCC is a feature of many airway diseases, including both genetic and acquired disorders. For example, in cystic fibrosis, mutations in the cystic fibrosis transmembrane conductance regulator protein result in a viscous, thick mucus that cannot be easily cleared, leading to repeated infections, bronchiectasis, and, eventually, respiratory failure (8). Primary ciliary dyskinesia is caused by genetic defects in the biogenesis, structure, or function of the motile cilia that line the respiratory tract (4,24).…”

Pharmacological Properties ofN-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N′-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine Methanesulfonate (552-02), a Novel Epithelial Sodium Channel Blocker with Potential Clinical Efficacy for Cystic Fibrosis Lung Disease

“…Emerging evidence suggests that CF lung pathophysiology is linked to dehydration of airway surfaces caused by epithelial ion transport defects (Baconnais et al, 2005;Boucher, 2007;Donaldson et al, 2007). One pharmacologic approach to rehydrate airway surfaces is aerosol ENaC blocker therapy.…”