Update in Cystic Fibrosis 2010
Authors: Peter J. Mogayzel, Patrick A. Flume
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

The role of ion transport in the maintenance of lung health is complex. The recent development of a porcine model of CF has the potential to provide a giant step forward in our understanding of the basic mechanisms whereby the loss of CF transmembrane conductance regulator (CFTR) function leads to parenchymal lung damage (2). These animals developed lung disease and demonstrated abnormal bacterial clearance in the absence of significant inflammation (3), suggesting that infection of the airways may be the primary event that initiates the progression of CF lung disease. How abnormalities in ion transport lead to an increased propensity for infection is unknown. Disruption of CFTR produces a defect in chloride and bicarbonate transport in porcine airway epithelium. However, the hyperabsorption of sodium and depletion of the airway surface liquid present in human airways was not observed in these newborn pigs (4). It is too early to say whether these differences in ion transport between human airways and the porcine model are species specific or are the result of other factors (e.g., age, inflammation). However, it may be that the lack of chloride (and/or bicarbonate) transport due to defective CFTR alone may be sufficient to cause lung disease, suggesting that correcting this defect is the appropriate goal of future therapies. Murine studies have also demonstrated that sodium hyperabsorption alone can lead to a CF phenotype (5). Taken together, these animal studies suggest that the relative roles of the chloride and sodium transport abnormalities in human disease are not yet fully defined. New data suggest that CFTR also plays an underappreciated role in airway development. Meyerholz and colleagues (6) found that trachea in CF pigs have a reduced diameter, abnormal smooth muscle, and hypoplastic submucosal glands. The authors postulate that submucosal gland abnormality may contribute to a host defense defect leading to a reduced ability to eradicate bacteria (3). However, the relevance of these findings to human disease is unclear because pathologic studies of human infants with CF failed to demonstrate submucosal gland hypoplasia (7, 8). Studies of recently developed CF ferret kits also show no reduction in glandular size compared with normal animals (9). A study by Bienvenu and colleagues (10) suggests that CFTR dysfunction can play a role in the development of airway abnormalities in the absence of two CF disease-causing mutations. They demonstrated abnormal sodium and chloride transport in 122 patients with diffuse non-CF bronchiectasis using nasal potential difference (NPD) measurements. The presence of 0 to 2 CFTR mutations was associated with a continuum of ion transport abnormalities, suggesting that the presence of at least one CFTR mutation may contribute to the development of disease. In the accompanying editorial, Boucher suggested the possibility that a second insult, in the setting of abnormal ion transport, may be responsible for the development of airways disease (11). The importance of ceramide in the regulation of cellular apoptosis and inflammatory responses is becoming more compelling. As we discussed last year (1), several investigators have suggested a role for ceramide in the development of CF lung disease, yet there remains controversy. Brodlie and colleagues (12) have provided additional support for the role for ceramide in CF lung disease. They found an increased amount of ceramide in the lower airways of explants removed at the time of transplantation from patients with CF compared with those with pulmonary hypertension or chronic obstructive pulmonary disease (COPD). Specifically, the C16:0, C18:0, and C20:0 species were significantly increased. There was a strong correlation between the presence of ceramide and neutrophilic inflammation. Becker and colleagues (13) confirmed the presence of increased ceramide accumulation in the airways of cftr-knockout mice. More importantly, they demonstrated that inhalation of acid sphingomyelinase inhibitors decreased the cellular ceramide concentrations and protected animals from Pseudomonas aeruginosa infection, suggesting that targeting this pathway may have significant therapeutic value. A difference of disease severity between sexes has long been known, with female patients with CF being at a survival disadvantage, but an explanation remains elusive (14, 15). Nick and colleagues (16) confirmed that the “gender gap” persists even in those who reach the age of 40 years, but paradoxically, for those patients diagnosed in adulthood, sex did not affect the rate of lung function decline, and women actually had a survival advantage. In an attempt to understand the effect of sex on CF, several investigators have studied hormonal influences on CFTR function. For example, Singh and colleagues (17) demonstrated that estrogens can directly interact with CFTR to decrease chloride transport. In 2010, Chotirmall and colleagues (18) postulated that effects of estrogen on inflammatory responses may put female patients with CF at a disadvantage during a portion of their menstrual cycle when hormonal effects can also influence airway surface liquid volume (19). They demonstrated that 17b-estradiol inhibits release of IL-8, perhaps by an increase in the expression of secretory leukoprotease inhibitor mediated through the b-isoform of the estrogen receptor.