Critical modifier role of membrane-cystic fibrosis transmembrane conductance regulator-dependent ceramide signaling in lung injury and emphysema

TitleCritical modifier role of membrane-cystic fibrosis transmembrane conductance regulator-dependent ceramide signaling in lung injury and emphysema
Publication TypeJournal Article
Year of Publication2011
AuthorsBodas M, Min T, Mazur S, Vij N
JournalJ Immunol
Volume186
Issue1
Pagination602-13
Date Published2011 Jan 1
ISSN1550-6606
KeywordsAcute Lung Injury, Aged, Animals, Cells, Cultured, Ceramides, Cystic Fibrosis Transmembrane Conductance Regulator, Disease Models, Animal, Down-Regulation, Female, HEK293 Cells, Humans, Lipopolysaccharides, Male, Membrane Microdomains, Mice, Mice, Inbred C57BL, Mice, Inbred CFTR, Mice, Knockout, Mice, Transgenic, Middle Aged, Pulmonary Disease, Chronic Obstructive, Pulmonary Emphysema, Severity of Illness Index, Signal Transduction, Up-Regulation
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.

DOI10.4049/jimmunol.1002850
Alternate JournalJ. Immunol.
PubMed ID21135173
PubMed Central IDPMC3119853
Grant ListP30 DK027651 / DK / NIDDK NIH HHS / United States
R03 HL096931 / HL / NHLBI NIH HHS / United States
R03 HL096931-01 / HL / NHLBI NIH HHS / United States
R03 HL096931-02 / HL / NHLBI NIH HHS / United States
RHL096931 / / PHS HHS / United States
UL RR 025005 / RR / NCRR NIH HHS / United States