Acquired Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction in Chronic Bronchitis and Other Diseases of Mucus Clearance

Abstract

Summary Chronic obstructive pulmonary disease (COPD) is a major public health problem accounting for more than 100,000 deaths and 750,000 hospitalizations each year in the United States alone. Though bronchodilators, inhaled steroids and other anti-inflammatory drugs can improve symptoms and reduce the risk of exacerbations, no therapies alter the natural history of the disease. This is the result of a number of factors including our poor understanding of the pathobiologic processes that drive specific COPD phenotypes, which has hindered drug development. Chronic bronchitis is perhaps the most clinically troublesome phenotype as most patients with COPD complain of cough and sputum production, and yet there are no effective treatments to target the mucus hypersecretion, accumulation and poor clearance that lead to these symptoms. Though it is well known that the absence of cystic fibrosis (CF) transmembrane receptor (CFTR) is the cause of CF, the prototypical disease of impaired mucociliary clearance, emerging data strongly suggest cigarette smoke and its components can lead to acquired CFTR dysfunction. Findings in vitro, in animal models, as well smokers with and without COPD also exhibit acquired CFTR dysfunction, which is associated with chronic bronchitis. This abnormality is not only present in the airways but is also present in extrapulmonary organs, suggesting CFTR dysfunction may contribute to smoking related lung disease as well as commonly associated comorbidities in which CFTR has a role. The development of potent CFTR modulators for the treatment of CF has made these findings clinically relevant as they may also have a role in treating COPD and other diseases of mucus clearance.

Use of low field nuclear magnetic resonance to monitor lung inflammation and the amount of pathological components in the sputum of cystic fibrosis patients

“…This effect may be even more relevant when applied to the monitoring of lung diseases more common than CF, that is, asthma and chronic obstructive pulmonary disease, which share many clinical and pathological features with CF, including abnormal sputum composition. 27,28 In this regard, preliminary data we obtained in asthma patients (unpublished results) confirm the validity of T 2m measurements in predicting lung ventilation.…”

Animal models of COPD: What do they tell us?

“…A few studies have used ferrets to recapitulate CS‐induced features of human COPD. Chronic CS exposure of ferrets for 6 months results in a reduction in cystic fibrosis transmembrane conductive regulator activity by 67% similar to that observed in COPD patients, which is associated with neutrophil inflammation, goblet cell hyperplasia and increased mucus production and emphysema . In other studies, CS exposure of ferrets has been used in studies related to the development of lung cancer .…”

The therapeutic potential of CFTR modulators for COPD and other airway diseases

“…The prior literature of CFTR dysfunction in response to cigarette-smoke exposure was previously reviewed [4]. …”

“…These trials also emphasize the importance of delineating the most appropriate patient phenotypes for future studies that involve differentiation based on baseline CFTR functional status (and/or CFTR genotype), severity of lung disease, smoking status, and level of concomitant emphysema and bronchiectasis [4,69]. …”