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Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A4

Abstract

The prevalence of asthma continues to increase and its optimal treatment remains a challenge. Here, we investigated the actions of lipoxin A4 (LXA4) and its leukocyte receptor in pulmonary inflammation using a murine model of asthma. Allergen challenge initiated airway biosynthesis of LXA4 and increased expression of its receptor. Administration of a stable analog of LXA4 blocked both airway hyper-responsiveness and pulmonary inflammation, as shown by decreased leukocytes and mediators, including interleukin-5, interleukin-13, eotaxin, prostanoids and cysteinyl leukotrienes. Moreover, transgenic expression of human LXA4 receptors in murine leukocytes led to significant inhibition of pulmonary inflammation and eicosanoid-initiated eosinophil tissue infiltration. Inhibition of airway hyper-responsiveness and allergic airway inflammation with a stable LXA4 analog highlights a unique counter-regulatory profile for the LXA4 system and its leukocyte receptor in airway responses. Moreover, our findings suggest that lipoxin and related pathways offer novel multi-pronged therapeutic approaches for human asthma.

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Figure 1: Inhibition of airway hyper-responsiveness with LXa.
Figure 2: Lung histopathology from LXa-treated mice.
Figure 3: LXa selectively inhibits airway leukocyte infiltration and inflammatory mediators.
Figure 4: In situ hybridization of murine ALX in lung.
Figure 5: Expression of human ALX in transgenic mice decreases pulmonary inflammation.
Figure 6: Expression of human ALX in tg mice prevents eosinophil trafficking.

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Acknowledgements

We thank M.H. Small for manuscript preparation, J. vom Saal for technical assistance and M. Loda of the Dana Farber/Harvard Cancer Center Pathology Core Facility. G.T.D.S. was a recipient of a Partners Investigator Nesson Award. This study was supported, in part, by National Institutes of Health grants K08-HL03788 (to B.D.L.), P50-HL56383 (to J.M.D. and B.D.L.), HL-36110 (to G.T.D.S.) and GM-38765, DK-50305 and P01-DE13499 (to C.N.S.).

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Correspondence to Charles N. Serhan.

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Levy, B., De Sanctis, G., Devchand, P. et al. Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A4. Nat Med 8, 1018–1023 (2002). https://doi.org/10.1038/nm748

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