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Role of CD95 in pulmonary inflammation and infection in cystic fibrosis

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Abstract

Cystic fibrosis is caused by a defective expression of the cystic fibrosis transmembrane conductance regulator (Cftr) gene, which results in chronic pulmonary inflammation and infections. The pathophysiological mechanisms by which these changes are induced in the lungs of patients with cystic fibrosis require definition. This study found that Cftr deficiency in mice results in the upregulation and activation of CD95. CD95 activation is caused by increased ceramide concentrations in cystic fibrosis lungs, as revealed by genetic modifications that normalize pulmonary ceramide concentrations. The activation of CD95 in cystic fibrosis lungs further increases pulmonary ceramide levels and results in a vicious feedback cycle of CD95 activation and ceramide accumulation. Genetic studies reveal that CD95 is crucially involved in the induction of aseptic inflammation, an increase in the bronchial cell death rate, and an increased susceptibility to infection of Cftr-deficient mice. All of these pathologies are partially corrected by heterozygosity of CD95 in Cftr-deficient mice. These findings identify CD95 as an important regulator of lung functions in cystic fibrosis and suggest that CD95 may be a novel target for treating cystic fibrosis.

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Acknowledgments

The authors thank M. Soddemann, S. Harde and B. Wilker for technical support. The study was supported by DFG grant Gu 335-16/2 to E.G.

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Authors and Affiliations

  1. Department of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany

    Katrin Anne Becker, Brian Henry, Regan Ziobro, Erich Gulbins & Heike Grassmé

  2. Clinical Research Group, OE6710, and Pediatric Pulmonology, Allergology and Neonatology, Department of Pediatrics and Adolescent Medicine, Hannover Medical School, Hannover, Germany

    Burkhard Tümmler

Authors
  1. Katrin Anne Becker
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  2. Brian Henry
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  3. Regan Ziobro
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  5. Erich Gulbins
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  6. Heike Grassmé
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Correspondence to Heike Grassmé.

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Becker, K.A., Henry, B., Ziobro, R. et al. Role of CD95 in pulmonary inflammation and infection in cystic fibrosis. J Mol Med 90, 1011–1023 (2012). https://doi.org/10.1007/s00109-012-0867-2

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  • DOI: https://doi.org/10.1007/s00109-012-0867-2

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