Protein-Lipid Link Common to Chronic Lung Disorders

Chronic lung diseases share a link between the ceramide class of lipids and the protein CFTR (cystic fibrosis transmembrane conductance regulator), which is present in a mutated and inactive form in cystic fibrosis.

Ceramides, which are composed of sphingosine and a fatty acid, are found in high concentrations within the cell membrane. They comprise one of the component lipids that constitute sphingomyelin, one of the major lipids in the lipid bilayer. In addition to a purely structural role, ceramide can act as a signaling molecule. The best-known functions of ceramides as cellular signals include regulating differentiation, proliferation, and apoptosis. Ceramide has also been shown to form organized large channels traversing the mitochondrial outer membrane. This leads to the migration of proteins from the intermembrane space.

How ceramide acts as a signaling molecule is not clear. One hypothesis is that ceramide generated in the plasma membrane stabilizes smaller lipid platforms known as lipid rafts, allowing them to serve as platforms for signaling molecules. Moreover, as rafts can cross the entire lipid bilayer, they can serve as the link between signals outside of the cell to signals to be generated within the cell.

In the current study, investigators at Johns Hopkins University (Baltimore, MD, USA) worked with a mouse model that included a line of mice that had been genetically engineered to lack the gene for CFTR. Findings from the mouse model were confirmed by analysis of tissues taken from humans with and without chronic lung disorders.

The investigators reported in the December 6, 2010, online edition of the Journal of Immunology that CFTR expression inversely correlated with the severity of emphysema and ceramide accumulation in chronic obstructive pulmonary disease subjects compared with control subjects. The lower the CFTR expression, the higher the level of ceramide and the more severe was the lung condition. Comparing normal and CFTR-deficient mice, they found that that membrane-CFTR was required for controlling lipid-raft ceramide levels.

Since low CFTR caused an increase in the level of ceramide, the investigators tested two drugs that inhibit ceramide synthesis on mice with lung damage caused by a bacterial infection. One of the inhibitors, FB1, successfully decreased ceramide buildup in mice with normal CFTR but did not prevent ceramide accumulation in mice lacking CFTR. The other drug, AMT, blocked ceramide increase in the mice lacking CFTR, while failing to do so in those with decreased CFTR.

"Our findings suggest that CFTR is a multitasker protein that is not only involved in chloride transport but also in regulating cell death and inflammation by keeping in check the rampant and dangerous accumulation of ceramide," said senior author Dr. Neeraj Vij, assistant professor of pediatrics at Johns Hopkins University. "We anticipate that membrane CFTR and ceramide may turn out to be useful predictors of susceptibility to lung damage from smoking and infections and may be tailored for drug therapy to alter disease course."

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