Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism
Lipoxin A4 stable analogs reduce allergic airway responses via mechanisms distinct from CysLT1 receptor antagonism
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DOI：
10.1096/fj.07-8653com
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发表时间：
2007-12-01
期刊：
影响因子：
4.8
通讯作者：
Parkinson, John F.
中科院分区：
文献类型：
--
作者：
Levy, Bruce D.;Lukacs, Nicholas W.;Parkinson, John F.
炎症/免疫反应期间的细胞募集受到严格调节。抑制炎症的能力对于预防慢性免疫反应（如哮喘）至关重要。在这里，我们研究了脂氧素 A(4) (LXA(4)) 稳定类似物在两种过敏原驱动的炎症模型中调节气道反应的能力。 15-epi-LXA(4) 类似物 (ATLa) 和 3-oxa-15-epi-LXA(4) 类似物 (ZK-994) 可防止小鼠用卵清蛋白致敏和气溶胶攻击后过量的嗜酸性粒细胞和 T 淋巴细胞积聚和激活。在 < 0.5 mg/kg 剂量下，这些 LXA4 类似物使进入肺部的白细胞运输减少了 > 50%，并且比同等剂量的 CysLT1 受体拮抗剂孟鲁司特减少的程度更大。与孟鲁司特不同，ATLa 治疗可显着降低半胱氨酰白三烯、白细胞介素 4 (IL-4) 和 IL-10，并且 ATLa 和 ZK-994 均抑制 IL-13 水平。在蟑螂过敏原诱导的气道反应中，腹膜内和口服 ZK-994 均以剂量依赖性方式显着降低气道炎症和高反应性参数。 ZK-994 还显着改变了 Th1/Th2 特异性细胞因子水平的平衡。因此，ATLa/LXA4类似物的作用与CysLT1拮抗作用不同，并且有效地阻断过敏性气道炎症和高反应性。此外，这些结果证明了这些类似物作为解决炎症的新激动剂的治疗潜力。
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 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.