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Lipoxin A₄ stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism

Bruce D. Levy^*,,1,2, Nicholas W. Lukacs^,2, Aaron A. Berlin, Birgitta Schmidt, William J. Guilford, Charles N. Serhan and John F. Parkinson^||,3

^* Pulmonary and Critical Care Medicine, Department of Internal Medicine and

Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA;

Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan, USA; and

Department of Medicinal Chemistry and

^|| Department of Immunology, Berlex Biosciences, Richmond, California, USA

¹Correspondence: Pulmonary and Critical Care Medicine, Thorn Bldg., Rm. 826a, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115, USA. E-mail: blevy{at}partners.org

Cellular recruitment during inflammatory/immune responses is tightly regulated. The ability to dampen inflammation is imperative for prevention of chronic immune responses, as in asthma. Here we investigated the ability of lipoxin A₄ (LXA₄) stable analogs to regulate airway responses in two allergen-driven models of inflammation. A 15-epi-LXA₄ analog (ATLa) and a 3-oxa-15-epi-LXA₄ analog (ZK-994) prevented excessive eosinophil and T lymphocyte accumulation and activation after mice were sensitized and aerosol-challenged with ovalbumin. At <0.5 mg/kg, these LXA₄ analogs reduced leukocyte trafficking into the lung by >50% and to a greater extent than equivalent doses of the CysLT1 receptor antagonist montelukast. Distinct from montelukast, ATLa treatment led to marked reductions in cysteinyl leukotrienes, interleukin-4 (IL-4), and IL-10, and both ATLa and ZK-994 inhibited levels of IL-13. In cockroach allergen-induced airway responses, both intraperitoneal and oral administration of ZK-994 significantly reduced parameters of airway inflammation and hyper-responsiveness in a dose-dependent manner. ZK-994 also significantly changed the balance of Th1/Th2-specific cytokine levels. Thus, the ATLa/LXA₄ analog actions are distinct from CysLT1 antagonism and potently block both allergic airway inflammation and hyper-reactivity. Moreover, these results demonstrate these analogs’ therapeutic potential as new agonists for the resolution of inflammation.—Levy, B. D., Lukacs, N. W., Berlin, A. A., Schmidt, B., Guilford, W. J., Serhan, C. N., Parkinson, J. F. Lipoxin A₄ stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism.

Key Words: resolution • lipid mediators • leukocytes

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