Editors' ChoiceCystic Fibrosis

Some Rozi for CF Too!

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Science Translational Medicine  24 Mar 2010:
Vol. 2, Issue 24, pp. 24ec46
DOI: 10.1126/scitranslmed.3001075

Cystic fibrosis (CF) is a genetic disease that results from mutation in the gene that encodes an apical ion channel in the epithelial cells, CF transmembrane conductance regulator (CFTR). Individuals that carry this mutation typically have a phenotype characterized by thick and sticky mucus production in the digestive tract and airways. Recent advances in treatment have made modest improvements in the quality and duration of life, but infection and inflammation of the lungs and intestine remain to be the primary cause of death in those with CF.

Animal models that inactivate CFTR do not exhibit typical lung disease; however, they still fail to survive as a result of mucus plugging of the intestines. Harmon et al. show in animal models of CF that intestinal epithelial cells and whole lung tissue are defective in peroxisome proliferator–activated receptor type γ (PPARγ) function. PPARγ dysfunction was shown to be correlated with decreased amounts of the fatty acid ligand 15-keto-PGE2, decreased expression of PPAR target genes, and increased expression of inflammatory cytokine genes. This phenotype was recapitulated in animal models with intestinal-specific deletion of PPARγ, further consolidating the involvement of this receptor. Treatment with PPAR agonist rosiglitazone was able to reverse the phenotypic effects caused by CFTR mutation, increase expression of PPAR target genes, and decrease inflammatory response genes. Although the effects of rosiglitazone did not affect CFTR channel function directly, an auxiliary set of genes that encode enzymes that increase bicarbonate secretion was responsive to rosiglitazone. Enhanced bicarbonate secretion subsequently increased mucus clearance.

The results obtained with rosiglitazone supplementation reduced intestinal obstruction and improved survival in mice in which CFTR had been knocked out. Whether the use of rosiglitazone will prove effective in human clinical studies remains to be seen; however, the reduction of inflammation and mucus retention—two main causes of CF morbidity—in animal models is encouraging.

G. S. Harmon et al., Pharmacological correction of a defect in PPAR-γ signaling ameliorates disease severity in Cftr-deficient mice. Nat. Med. 16, 313–318 (2010). [Full Text]

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