Autotaxin Production of Lysophosphatidic Acid Mediates Allergic Asthmatic Inflammation
Autotaxin Production of Lysophosphatidic Acid Mediates Allergic Asthmatic Inflammation
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DOI：
10.1164/rccm.201306-1014oc
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发表时间：
2013-10-15
影响因子：
24.7
通讯作者：
Christman, John W.
中科院分区：
文献类型：
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作者：
Park, Gye Young;Lee, Yong Gyu;Christman, John W.
原理：来源于膜脂前体的生物活性脂质介体被释放到呼吸道和腔隙，在那里它们与高亲和力同源受体结合，可能介导哮喘的发病。溶血磷脂酸(LPA)是一种由细胞外自体趋化蛋白(ATX)的酶活性产生的生物活性脂质介质，它与LPA受体结合，对细胞的增殖、迁移、存活、分化和运动产生一系列的生物学作用，从而介导哮喘的发病。目的：明确ATX-LPA通路在人类哮喘发病机制和过敏性肺炎症模型中的作用。方法：观察过敏原对哮喘患者支气管肺泡灌洗液中LPA分子种类和ATX外酶的影响。我们利用ATX-LPA途径特异性转基因小鼠的过敏性哮喘小鼠模型，研究了ATX-LPA途径在变态反应性肺部炎症中的作用。测量和主要结果：轻度哮喘患者用变应原刺激亚段支气管导致富含多不饱和脂肪酸22：5和22：6的支气管肺泡灌洗液中LPA水平显著增加，并与ATX蛋白浓度增加有关。利用三变应原小鼠哮喘模型，我们发现ATX过表达的转基因小鼠具有更严重的哮喘表型，而阻断ATX活性和敲除LPA2受体可显著降低Th2细胞因子和过敏性肺部炎症。结论：ATX-LPA通路在哮喘的发病机制中起关键作用。这些临床前数据表明，靶向ATX-LPA通路可能是一种有效的抗哮喘治疗策略。
Rationale: Bioactive lipid mediators, derived from membrane lipid precursors, are released into the airway and airspace where they bind high-affinity cognate receptors and may mediate asthma pathogenesis. Lysophosphatidic acid (LPA), a bioactive lipid mediator generated by the enzymatic activity of extracellular autotaxin (ATX), binds LPA receptors, resulting in an array of biological actions on cell proliferation, migration, survival, differentiation, and motility, and therefore could mediate asthma pathogenesis.Objectives: To define a role for the ATX-LPA pathway in human asthma pathogenesis and a murine model of allergic lung inflammation.Methods: We investigated the profiles of LPA molecular species and the level of ATX exoenzyme in bronchoalveolar lavage fluids of human patients with asthma subjected to subsegmental bronchoprovocation with allergen. We interrogated the role of the ATX-LPA pathway in allergic lung inflammation using a murine allergic asthma model in ATX-LPA pathway-specific genetically modified mice.Measurements and Main Results: Subsegmental bronchoprovocation with allergen in patients with mild asthma resulted in a remarkable increase in bronchoalveolar lavage fluid levels of LPA enriched in polyunsaturated 22: 5 and 22: 6 fatty acids in association with increased concentrations of ATX protein. Using a triple-allergen mouse asthma model, we showed that ATX-overexpressing transgenic mice had a more severe asthmatic phenotype, whereas blocking ATX activity and knockdown of the LPA2 receptor in mice produced a marked attenuation of Th2 cytokines and allergic lung inflammation.Conclusions: The ATX-LPA pathway plays a critical role in the pathogenesis of asthma. These preclinical data indicate that targeting the ATX-LPA pathway could be an effective antiasthma treatment strategy.