Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism.
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
Bruce D
BD
Department of Internal Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. blevy@partners.org
Lukacs
Nicholas W
NW
Berlin
Aaron A
AA
Schmidt
Birgitta
B
Guilford
William J
WJ
Serhan
Charles N
CN
Parkinson
John F
JF
D000085:Acetates / Q000494:pharmacology; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D052179:Antigens, Plant; D003521:Cyclopropanes; D004195:Disease Models, Animal; D020024:Leukotriene Antagonists / Q000494:pharmacology; D044045:Lipoxins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010647:Phenyl Ethers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D018077:Receptors, Leukotriene / Q000502:physiology; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000517:prevention & control*; D013329:Structure-Activity Relationship; D013440:Sulfides
C485114:16-(4-fluorophenoxy)-3-oxa-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoic acid; D000085:Acetates; D000485:Allergens; D018927:Anti-Asthmatic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052179:Antigens, Plant; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D044045:Lipoxins; D008565:Membrane Proteins; D010647:Phenyl Ethers; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; C060835:allergen CRa, cockroach; C040527:lipoxin A4; D010047:Ovalbumin; C083169:leukotriene D4 receptor; C093875:montelukast