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

BD Levy, NW Lukacs, AA Berlin, B Schmidt… - The FASEB journal …, 2007 - ncbi.nlm.nih.gov
BD Levy, NW Lukacs, AA Berlin, B Schmidt, WJ Guilford, CN Serhan, JF Parkinson
The FASEB journal: official publication of the Federation of American …, 2007ncbi.nlm.nih.gov
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 A 4 (LXA 4) stable analogs to regulate
airway responses in two allergen-driven models of inflammation. A 15-epi-LXA 4 analog
(ATLa) and a 3-oxa-15-epi-LXA 4 analog (ZK-994) prevented excessive eosinophil and T
lymphocyte accumulation and activation after mice were sensitized and aerosol-challenged …
Abstract
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 A 4 (LXA 4) stable analogs to regulate airway responses in two allergen-driven models of inflammation. A 15-epi-LXA 4 analog (ATLa) and a 3-oxa-15-epi-LXA 4 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 LXA 4 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/LXA 4 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.
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