Nature Medicine8, 1018 - 1023 (2002)
Published online: 12 August 2002; | doi:10.1038/nm748
Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A4
Bruce D. Levy1, 2, George T. De Sanctis2, Pallavi R. Devchand1, Eugene Kim1, Kate Ackerman2, Birgitta A. Schmidt1, Wojciech Szczeklik1, Jeffrey M. Drazen2
& Charles N. Serhan1
1
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Boston, Massachusetts, USA
2
Pulmonary and Critical Care Medicine, Department of Internal Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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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