Reduced expression of the Ion channel CFTR contributes to airspace enlargement as a consequence of aging and in response to cigarette smoke in mice

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is a complex disease resulting in respiratory failure and represents the third leading cause of global death. The two classical phenotypes of COPD are chronic bronchitis and emphysema. Owing to similarities between chronic bronchitis and the autosomal-recessive disease Cystic Fibrosis (CF), a significant body of research addresses the hypothesis that dysfunctional CF Transmembrane Conductance Regulator (CFTR) is implicated in the pathogenesis of COPD. Much less attention has been given to emphysema in this context, despite similarities between the two diseases. These include early-onset cellular senescence, similar comorbidities, and the finding that CF patients develop emphysema as they age. To determine a potential role for CFTR dysfunction in the development of emphysema, Cftr +/+ (Wild-type; WT), Cftr +/− (heterozygous), and Cftr −/− (knock-out; KO) mice were aged or exposed to cigarette smoke and analyzed for airspace enlargement. Aged knockout mice demonstrated increased alveolar size compared to age-matched wild-type and heterozygous mice. Furthermore, both heterozygous and knockout mice developed enlarged alveoli compared to their wild-type counterparts following chronic smoke exposure. Taken into consideration with previous findings that cigarette smoke leads to reduced CFTR function, our findings suggest that decreased CFTR expression sensitizes the lung to the effects of cigarette smoke. These findings may caution normally asymptomatic CF carriers against exposure to cigarette smoke; as well as highlight emphysema as a future challenge for CF patients as they continue to live longer. More broadly, our data, along with clinical findings, may implicate CFTR dysfunction in a pathology resembling accelerated aging.

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

“…Regarding the significant prevalence of loss-of-function CFTR alleles/variants in the most severe clinical categories, the finding is in accordance with our previous work [ 17 ] and the work of others [ 45 ] showing that carriers of single pathogenic CFTR variants are more likely to undergo severe COVID-19 with a high risk of 14-day mortality [ 17 ]). Estrogen levels and the reported reduced CFTR expression as a consequence of aging [ 46 ] may further contribute to the severity of COVID-19 disease in older men and women. Interestingly, it was recently proposed in a preprint that the coronavirus spike protein may bind to CFTR, inhibiting its activity [ 22 ] and that the SARS-CoV-2 nucleocapsid protein could interact with Smad3, which downregulated CFTR expression via microRNA-145 [ 23 ].…”

Dysfunction in the Cystic Fibrosis Transmembrane Regulator in Chronic Obstructive Pulmonary Disease as a Potential Target for Personalised Medicine

“…As a consequence, the cough mechanism increases to try to compensate for this deficit, with an increase in coughing and chronic expectoration, which is called chronic bronchitis [46]. On the other hand, as mentioned above, in patients with emphysema, there is a correlation between the spirometric values of lung function and CFTR [45], Interestingly, a recent murine model shows the contribution of a reduced expression of CFTR and airspace enlargement [47].…”

The Potential Role and Regulatory Mechanisms of MUC5AC in Chronic Obstructive Pulmonary Disease

“…The CFTR protein functions as an anion channel on the apical surface of airway epithelia and mutation in CFTR cause aberrant Cl - and Na + transport, leading to airway mucus dehydration and hypersecretion. Impaired CFTR function compromises mucociliary clearance, leads to airway obstruction and chronic airway infection, with Gram-negative bacteria such as P. aeuroginosa causing respiratory failure [ 80 ]. CFTR belongs to the ATP-binding cassette (ABC) subfamily of transporters.…”