Age-Dependent Progression in Lung Pathophysiology can be Prevented by Restoring Fatty Acid and Ceramide Imbalance in Cystic Fibrosis

Lung. 2020 Jun;198(3):459-469. doi: 10.1007/s00408-020-00353-2. Epub 2020 Apr 18.


Purpose: Cystic fibrosis (CF) is a progressive disease which causes a continuous decline in lung capacity with age. Our study aimed to investigate the age-dependent deterioration in lung function and the effects of treatment with Fenretinide formulation (LAU-7b) in Cftr knockout (KO) mice.

Methods: Non-invasive whole-body plethysmography (WBP) was done to measure the baseline lung functions of KO and wild-type (WT) mice at the ages of 2 and 4 months. Mice were then treated for 21 days with PBS or 10 mg/kg/day LAU-7b initiated at 4 and 7 months. Standard airway resistance measurements, haematoxylin and eosin staining, and analysis of lipids, and markers of oxidation were performed.

Results: The 4- and 7-month-old KO mice had significantly higher lung enhanced pause (Penh) and resistance values than age-matched WT mice and 2-month-old KO mice. Likewise, analysis of ceramides showed that PBS-treated mice had higher levels of long-chain ceramides (LCCs; C14-C18) and lower levels of very-long-chain ceramides (VLCCs; C24-C26) compared to LAU-7b-treated mice. Cftr KO mice displayed markedly greater inflammatory cell infiltration and epithelial hyperplasia at the ages of 2, 4, and 7 months compared to WT. LAU-7b treatment significantly diminished this cellular infiltration and epithelial hyperplasia compared to PBS-treated mice.

Conclusion: Our results demonstrate a progressive age-dependent decline in lung function in Cftr KO mice. Treatment with LAU-7b corrects the lipid imbalance observed in the aging KO and WT mice and, more importantly, inhibits the age-dependent deterioration in lung physiology and histopathology.

Keywords: Airways inflammation; Ceramide imbalance; Cftr knockout mice; Cystic fibrosis; Fatty acids; LAU-7b.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Aging*
  • Airway Resistance / physiology*
  • Animals
  • Ceramides / metabolism*
  • Chromatography, High Pressure Liquid
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis / physiopathology*
  • Disease Models, Animal
  • Disease Progression
  • Fatty Acids / metabolism*
  • Lung / physiopathology*
  • Mice
  • Mice, Knockout
  • Plethysmography


  • Ceramides
  • Fatty Acids

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