Drug Discovery Opinion

Cystic fibrosis (CF) results from a genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) that results in impaired transport of chloride and bicarbonate ions. Patients with CF have thickened mucus, accompanied by inflammation, which affects the lungs and organs of the intestinal tract. Although the disease has received much scientific attention, current treatments only manage the symptoms and affected individuals continue to suffer from reduced life expectancy.

A new study from researchers at University of California, San Diego School of Medicine, has now identified defects in signalling mediated by peroxisome proliferator-activated receptor-γ (PPAR-γ) that contribute to disease symptoms. Examining colonic epithelial cells and whole lung tissue from CFTR-deficient mice, the team found reduced expression of genes that are normally activated by PPAR-γ. Lipidomic analysis of the colonic epithelial cells suggested that the defect resulted in part from reduced amounts of the endogenous PPAR-γ ligand, 15-keto-prostaglandin E₂ (15-keto-PGE₂). The researchers were able to partially restore gene expression by treating the mice with rosiglitazone, a PPAR-γ agonist used in the treatment of diabetes, reducing the severity of disease.

Rosiglitazone had no effect on chloride secretion in the colon, but increased expression of carbonic anhydrases 2 and 4 (Car2 and Car4) resulting in increased bicarbonate secretion and reduced mucus retention.

The study, published in Nature Medicine, suggests that levels of 15-keto-PGE₂ could provide a marker for patients who might benefit from treatment with a PPAR-γ agonist.

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