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

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Abstract

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.

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Funding

This research has been supported by Cystic Fibrosis Canada Grant #494470 to BP, DR; ENOCH Molecular, cellular and clinical approach to healthy ageing grant ENOCH; Registration Number: CZ.02.1.01/0.0/0.0/16_019/ 0000868 MH, DR, JdS. CIHR Grant FRN115117 #2433990; RI-MUHC Account 4925 to DR.

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Author notes

  1. Juhi Shah and Daciana Catalina Dumut have contributed equally to this work.

Authors and Affiliations

  1. Department of Human Genetics, McGill University, McGill University, Montreal, QC, Canada

    Mina Youssef & Danuta Radzioch

  2. Program in Infectious Diseases and Immunity in Global Health, McGill University Health Centre, 1001 Decarie Boulevard, Room EM3-3211, Montreal, QC, H4A 3J1, Canada

    Mina Youssef, Juhi Shah, Daciana Catalina Dumut & Danuta Radzioch

  3. Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic

    Juan B. De Sanctis, Marian Hajduch & Danuta Radzioch

  4. Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada

    Juhi Shah

  5. Department of Medicine, Division of Experimental Medicine, McGill University, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada

    Daciana Catalina Dumut, Basil J. Petrof & Danuta Radzioch

  6. Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada

    Basil J. Petrof

Authors
  1. Mina Youssef
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Corresponding author

Correspondence to Danuta Radzioch.

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Conflict of interest

The corresponding author, Dr. Radzioch, Principal Investigator at the Research Institute of the McGill University Health Centre and Professor at McGill University, is a minor shareholder of Laurent Pharmaceuticals Inc. which generously (free of charge) provided the clinical capsules used for treatment of Cftr KO mice and their littermate controls. The studies presented have not been otherwise financially supported by Laurent Pharmaceuticals Inc. and neither the first author nor any other co-author have any conflicts of interest to declare associated with this publication.

Ethical Approval

All experimental procedures were conducted in accordance with and approval of the Animal Care Committee of the McGill University Health Centre, Montreal, Quebec, Canada.

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Youssef, M., De Sanctis, J.B., Shah, J. et al. Age-Dependent Progression in Lung Pathophysiology can be Prevented by Restoring Fatty Acid and Ceramide Imbalance in Cystic Fibrosis. Lung 198, 459–469 (2020). https://doi.org/10.1007/s00408-020-00353-2

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  • DOI: https://doi.org/10.1007/s00408-020-00353-2

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