Critical Modifier Role of Membrane-Cystic Fibrosis Transmembrane Conductance Regulator-Dependent Ceramide Signaling in Lung Injury and Emphysema

Abstract

Ceramide accumulation mediates the pathogenesis of chronic obstructive lung diseases. Although an association between lack of cystic fibrosis transmembrane conductance regulator (CFTR) and ceramide accumulation has been described, it is unclear how membrane-CFTR may modulate ceramide signaling in lung injury and emphysema. Cftr+/+ and Cftr−/− mice and cells were used to evaluate the CFTR-dependent ceramide signaling in lung injury. Lung tissue from control and chronic obstructive pulmonary disease patients was used to verify the role of CFTR-dependent ceramide signaling in pathogenesis of chronic emphysema. Our data reveal that CFTR expression inversely correlates with severity of emphysema and ceramide accumulation in chronic obstructive pulmonary disease subjects compared with control subjects. We found that chemical inhibition of de novo ceramide synthesis controls Pseudomonas aeruginosa-LPS–induced lung injury in Cftr+/+ mice, whereas its efficacy was significantly lower in Cftr−/− mice, indicating that membrane-CFTR is required for controlling lipid-raft ceramide levels. Inhibition of membrane-ceramide release showed enhanced protective effect in controlling P. aeruginosa-LPS–induced lung injury in Cftr−/− mice compared with that in Cftr+/+ mice, confirming our observation that CFTR regulates lipid-raft ceramide levels and signaling. Our results indicate that inhibition of de novo ceramide synthesis may be effective in disease states with low CFTR expression like emphysema and chronic lung injury but not in complete absence of lipid-raft CFTR as in ΔF508-cystic fibrosis. In contrast, inhibiting membrane-ceramide release has the potential of a more effective drug candidate for ΔF508-cystic fibrosis but may not be effectual in treating lung injury and emphysema. Our data demonstrate the critical role of membrane-localized CFTR in regulating ceramide accumulation and inflammatory signaling in lung injury and emphysema.

Cystic Fibrosis Transmembrane Conductance Regulator Activation by Roflumilast Contributes to Therapeutic Benefit in Chronic Bronchitis

“…Although WCS has been frequently used to model smoking-related lung disease (24,29) and the reduced CFTR function observed here is consistent with prior studies (2,9,24,29), the experiments conducted rely on acute CSE and are unlikely to capture the complexity of the airway environment in patients with COPD, such as airway inflammation, disrupted proteolytic balance, and ER stress (3,31,47,48). Although the conclusion that CFTR activation by roflumilast contributes to therapeutic benefit in patients with chronic bronchitis is supported by specificity controls, as an efficacious activator of intracellular cAMP, roflumilast may also improve the function of surface epithelia via other pathways.…”

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

“…Our data do not support the increase in lymphocyte numbers to have occurred as a result of an enhanced proliferative response of lymphocytes from Cftr tm1UNC mice, as this was not different from WT levels, in agreement with prior reports of this phenotype in cells from B6 Cftr tm1UNC mice (20,21). There is, however, some discrepancy in this literature, as Bodas et al (39) reported splenocytes from older (24 wk old) B6 Cftr tm1Kth mice to have an increased proliferative response to Con A challenge, a stimulus different from the CD3 used in the present study. Because an inherent capacity for increased proliferation is unlikely to have contributed to the CD3 + levels in the lungs of BALB Cftr tm1UNC mice, epithelial-derived cytokine secretions may have, as indicated by Al Alam et al (40), who showed that FIGURE 2.…”

CFTR: cystic fibrosis and beyond

“…1) [48,50]. Moreover, recent studies found an association between CFTR expression, ceramide accumulation and severity of emphysema in COPD patients [133]. In addition, studies in mice showed that cigarette smoke decreases CFTR levels in lipid rafts, and that CFTR is implicated in apoptotic and autophagic responses in cigarette smoke-induced lung epithelial injury [134].…”