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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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References

  1. Welch, W.J., Ramsey, B.W., Accurso, F.J. & Cutting, G.R. in Metabolic and Molecular Bases of Inherited Disease (eds. Scriver, C.R. et al.) 521–588 (McGraw-Hill, New York, 2001).

    Google Scholar 

  2. Verkman, A.S., Song, Y. & Thiagarajah, J.R. Role of airway surface liquid and submucosal glands in cystic fibrosis lung disease. Am. J. Physiol. Cell Physiol. 284, C2–C15 (2003).

    Article  CAS  Google Scholar 

  3. Khan, T.Z. et al. Early pulmonary inflammation in infants with cystic fibrosis. Am. J. Respir. Crit. Care Med. 151, 1075–1082 (1995).

    CAS  PubMed  Google Scholar 

  4. Bonfield, T.L. et al. Inflammatory cytokines in cystic fibrosis lungs. Am. J. Respir. Crit. Care Med. 152, 2111–2118 (1995).

    Article  CAS  Google Scholar 

  5. Muhlebach, M.S., Stewart, P.W., Leigh, M.W. & Noah, T.L. Quantitation of inflammatory responses to bacteria in young cystic fibrosis and control patients. Am. J. Respir. Crit. Care Med. 160, 186–191 (1999).

    Article  CAS  Google Scholar 

  6. Noah, T.L., Black, H.R., Cheng, P.W., Wood, R.E. & Leigh, M.W. Nasal and bronchoalveolar lavage fluid cytokines in early cystic fibrosis. J. Infect. Dis. 175, 638–647 (1997).

    Article  CAS  Google Scholar 

  7. Tirouvanziam, R. et al. Inflammation and infection in naive human cystic fibrosis airway grafts. Am. J. Respir. Cell Mol. Biol. 23, 121–127 (2000).

    Article  CAS  Google Scholar 

  8. Muhlebach, M.S. & Noah, T.L. Endotoxin activity and inflammatory markers in the airways of young patients with cystic fibrosis. Am. J. Respir. Crit. Care Med. 165, 911–915 (2002).

    Article  Google Scholar 

  9. Konstan, M.W., Walenga, R.W., Hilliard, K.A. & Hilliard, J.B. Leukotriene B4 markedly elevated in the epithelial lining fluid of patients with cystic fibrosis. Am. Rev. Respir. Dis. 148, 896–901 (1993).

    Article  CAS  Google Scholar 

  10. McElvaney, N.G. et al. Aerosol α1-antitrypsin treatment for cystic fibrosis. Lancet 337, 392–394 (1991).

    Article  CAS  Google Scholar 

  11. Rosenberg, H.F. & Gallin, J.I. in Fundamental Immunology 4th edn. (ed. Paul, W.E.) 1051–1066 (Lippincott-Raven, Philadelphia, 1999).

    Google Scholar 

  12. Serhan, C.N. Lipoxins and aspirin-triggered 15-epi-lipoxin biosynthesis: an update and role in anti-inflammation and pro-resolution. Prostaglandins Other Lipid Mediat. 69, 433–455 (2002).

    Article  Google Scholar 

  13. Fierro, I.M. & Serhan, C.N. Mechanisms in anti-inflammation and resolution: the role of lipoxins and aspirin-triggered lipoxins. Braz. J. Med. Biol. Res. 34, 555–566 (2001).

    Article  CAS  Google Scholar 

  14. Gewirtz, A.T. et al. Pathogen-induced chemokine secretion from model intestinal epithelium is inhibited by lipoxin A4 analogs. J. Clin. Invest. 101, 1860–1869 (1998).

    Article  CAS  Google Scholar 

  15. Clish, C.B. et al. Local and systemic delivery of a stable aspirin-triggered lipoxin prevents neutrophil recruitment in vivo . Proc. Natl. Acad. Sci. USA 96, 8247–8252 (1999).

    Article  CAS  Google Scholar 

  16. van Heeckeren, A.M. & Schluchter, M.D. Murine models of chronic Pseudomonas aeruginosa lung infection. Lab Anim. 36, 291–312 (2002).

    Article  CAS  Google Scholar 

  17. Costerton, J.W. Cystic fibrosis pathogenesis and the role of biofilms in persistent infection. Trends Microbiol. 9, 50–52 (2001).

    Article  CAS  Google Scholar 

  18. Stotland, P.K., Radzioch, D. & Stevenson, M.M. Mouse models of chronic lung infection with Pseudomonas aeruginosa: models for the study of cystic fibrosis. Pediatr. Pulmonol. 30, 413–424 (2000).

    Article  CAS  Google Scholar 

  19. Bonnans, C. et al. Lipoxins are potential endogenous antiinflammatory mediators in asthma. Am. J. Respir. Crit. Care Med. 165, 1531–1535 (2002).

    Article  Google Scholar 

  20. Sanak, M. et al. Aspirin-tolerant asthmatics generate more lipoxins than aspirin-intolerant asthmatics. Eur. Respir. J. 16, 44–49 (2000).

    Article  CAS  Google Scholar 

  21. Hopen, U.E., Lu, B., Gerard, N.P. & Gerard, C. The C5a chemoattractant receptor mediates mucosal defense to infection. Nature 383, 25–26 (1996).

    Article  Google Scholar 

  22. Bonnans, C., Mainprice, B., Chanez, P., Bousquet, J. & Urbach, V. Lipoxin A4 stimulates a cytosolic Ca2+ increase in human bronchial epithelium. J. Biol. Chem. 278, 10879–10884 (2003).

    Article  CAS  Google Scholar 

  23. Pilewski, J.M. & Frizzell, R.A. Role of CFTR in airway disease. Physiol. Rev. 79, S215–S255 (1999).

    Article  CAS  Google Scholar 

  24. Serhan, C.N., Levy, B.D., Clish, C.B., Gronert, K. & Chiang, N. Lipoxins, aspirin triggered 15-epi-lipoxin stable analogs and their receptors in anti-inflammation: a window for therapeutic opportunity. Ernst Schering Res. Found. Workshop 31, 143–185 (2000).

    CAS  Google Scholar 

  25. Levy, B.D., Clish, C.B., Schmidt, B., Gronert, K. & Serhan, C.N. Lipid mediator class switching during acute inflammation: signals in resolution. Nat. Immunol. 2, 612–619 (2001).

    Article  CAS  Google Scholar 

  26. Xu, Y. et al. Transcriptional adaptation to cystic fibrosis transmembrane conductance regulator deficiency. J. Biol. Chem. 278, 7674–7682 (2003).

    Article  CAS  Google Scholar 

  27. Hong, S., Gronert, K., Devchand, P.R., Moussignac, R.L. & Serhan, C.N. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. J. Biol. Chem. 278, 14677–14687 (2003).

    Article  CAS  Google Scholar 

  28. Serhan, C.N. et al. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J. Exp. Med. 192, 1197–1204 (2000).

    Article  CAS  Google Scholar 

  29. Serhan, C.N. et al. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J. Exp. Med. 196, 1025–1037 (2002).

    Article  CAS  Google Scholar 

  30. Freedman, S.D., Shea, J.C., Blanco, P.G. & Alvarez, J.G. Fatty acids in cystic fibrosis. Curr. Opin. Pulm. Med. 6, 530–532 (2000).

    Article  CAS  Google Scholar 

  31. Freedman, S.D. et al. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N. Engl. J. Med. 350, 560–569 (2004).

    Article  CAS  Google Scholar 

  32. Gronert, K., Gewirtz, A., Madara, J.L. & Serhan, C.N. Identification of a human enterocyte lipoxin A4 receptor that is regulated by interleukin (IL)-13 and interferon γ and inhibits tumor necrosis factor α-induced IL-8 release. J. Exp. Med. 187, 1285–1294 (1998).

    Article  CAS  Google Scholar 

  33. Gronert, K., Martinsson-Niskanen, T., Ravasi, S., Chiang, N. & Serhan, C.N. Selectivity of recombinant human leukotriene D4, leukotriene B4, and lipoxin A4 receptors with aspirin-triggered 15-epi-LXA4 and regulation of vascular and inflammatory responses. Am. J. Pathol. 158, 3–9 (2001).

    Article  CAS  Google Scholar 

  34. Sarau, H.M. et al. Identification, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor. Mol. Pharmacol. 56, 657–663 (1999).

    Article  CAS  Google Scholar 

  35. Lynch, K.R. et al. Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 399, 789–793 (1999).

    Article  CAS  Google Scholar 

  36. Wills-Karp, M. et al. Interleukin-13: central mediator of allergic asthma. Science 282, 2258–2261 (1998).

    Article  CAS  Google Scholar 

  37. Gewirtz, A.T. et al. Lipoxin A4 analogs attenuate induction of intestinal epithelial proinflammatory gene expression and reduce the severity of dextran sodium sulfate-induced colitis. J. Immunol. 168, 5260–5267 (2002).

    Article  CAS  Google Scholar 

  38. Andrews, P.C. & Krinsky, N.L. Quantitative determination of myeloperoxidase using tetramethylbenzidine as substrate. Anal. Biochem. 127, 346–350 (1982).

    Article  CAS  Google Scholar 

Download references

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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