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Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway

Nature Immunology volume 5, pages 388–392 (2004)Cite this article

Abstract

In cystic fibrosis, dysregulated neutrophilic inflammation and chronic infection lead to progressive destruction of the airways. The underlying mechanisms have remained unclear. Lipoxins are anti-inflammatory lipid mediators that modulate neutrophilic inflammation. We report here that lipoxin concentrations in airway fluid were significantly suppressed in patients with cystic fibrosis compared to patients with other inflammatory lung conditions. We also show that administration of a metabolically stable lipoxin analog in a mouse model of the chronic airway inflammation and infection associated with cystic fibrosis suppressed neutrophilic inflammation, decreased pulmonary bacterial burden and attenuated disease severity. These findings suggest that there is a pathophysiologically important defect in lipoxin-mediated anti-inflammatory activity in the cystic fibrosis lung and that lipoxins have therapeutic potential in this lethal autosomal disease.

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Figure 1: LXA4/neutrophil and IL-8/neutrophil ratios in BAL fluids from stable patients with cystic fibrosis and patients with other inflammatory lung conditions.
Figure 2: Lipoxin A4 analog inhibits P. aeruginosa–mediated IL-8 secretion by primary human bronchial epithelial cells.
Figure 3: Lipoxin A4 analog treatment leads to suppression of neutrophilic inflammation and a shift to 'chronic' inflammation in the airways of mice challenged with mucoid P. aeruginosa.
Figure 4: Lipoxin A4 analog treatment leads to suppression of neutrophil accumulation in the lung parenchyma after challenge with P. aeruginosa.
Figure 5: Lipoxin A4 analog treatment leads to a decrease in lung bacterial burden after challenge with P. aeruginosa.
Figure 6: Lipoxin A4 analog treatment ameliorates disease course in mice challenged with P. aeruginosa.

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Acknowledgements

We thank A. van Heeckeren for providing P. aeruginosa strain M57-15. Supported by the Cystic Fibrosis Foundation (KARP01G0, NCRR M01 RR00069, and the Johns Hopkins and Cincinnati Children's Hospital Medical Center CF Research Development Program Centers).

Author information

Author notes

  1. Leah M Flick, Kiwon W Park and Samir Softic: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, and University of Cincinnati College of Medicine, Cincinnati, 45229, Ohio, USA

    Christopher L Karp, Leah M Flick, Samir Softic, Todd M Greer, Sowsan F Atabani & Yasmine Belkaid

  2. Department of Molecular Microbiology and Immunology, Johns Hopkins University, Baltimore, 21287, Maryland, USA

    Kiwon W Park

  3. Department of Chemistry, University of Southern California, Los Angeles, 90089, California, USA

    Raquel Keledjian, Rong Yang, Jasim Uddin & Nicos A Petasis

  4. Department of Physiology, Johns Hopkins University, Baltimore, 21287, Maryland, USA

    William B Guggino

  5. Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, and University of Cincinnati College of Medicine, Cincinnati, 45229, Ohio, USA

    Yan Xu & Jeffrey A Whitsett

  6. Department of Pediatrics, University of Colorado Health Sciences Center, Mike McMorris Cystic Fibrosis Research and Treatment Center, the Children's Hospital, Denver, 80218, Colorado, USA

    Frank J Accurso

  7. Division of Immunobiology, Cincinnati Children's Hospital Medical Center, and University of Cincinnati College of Medicine, Cincinnati, 45229, Ohio, USA

    Marsha Wills-Karp

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Correspondence to Christopher L Karp.

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Karp, C., Flick, L., Park, K. et al. Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway. Nat Immunol 5, 388–392 (2004). https://doi.org/10.1038/ni1056

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