Dysregulated synthesis of protectin D1 in eosinophils from patients with severe asthma

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• 作者：Jun Miyata ; MD^a ; Koichi Fukunaga ; MD ; PhD^a ; Ryo Iwamoto ; MS^b ; Yosuke Isobe ; MS^b ; ^c ; Kyoko Niimi ; MD^a ; Rina Takamiya ; PhD^a ; Takahisa Takihara ; MD^a ; Katsuyoshi Tomomatsu ; MD^a ; ^d ; Yusuke Suzuki ; MD^a ; Tsuyoshi Oguma ; MD^a ; ^d ; Koichi Sayama ; MD^a ; Hiroyuki Arai ; PhD^c ; Tomoko Betsuyaku ; MD ; PhD^a ; Makoto Arita ; PhD^c ; Koichiro Asano ; MD^a ; ^d ; ^{ko-asano@tokai-u.jp}
• 关键词：Asthma ; CCL11 ; docosahexaenoic acid ; 15-lipoxygenase ; 5-oxo-eicosatetraenoic acid ; IL-5 ; lipid mediator ; platelet-activating factor
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2013
• 出版时间：February, 2013
• 年：2013
• 卷：131
• 期：2
• 页码：353-360.e2
• 全文大小：1460 K

文摘

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Background

Protectin D1 (PD1) is an anti-inflammatory and proresolving lipid mediator biosynthesized from the omega-3 fatty acid docosahexaenoic acid (DHA). Exogenous PD1 conferred protection against eosinophilic inflammation in animals with experimental asthma, although its endogenous cellular source and functions in human airways are of interest.

Objective

We sought to investigate the synthesizing capacity of PD1 in eosinophils from healthy subjects and patients with severe asthma and its direct effects on eosinophil functions.

Methods

Human eosinophil-derived metabolites of arachidonic acid and DHA were analyzed with liquid chromatography-tandem mass spectrometry-based lipidomic analysis. The biological activities of PD1 on the function of human eosinophils, including chemotaxis, adhesion molecule expressions, degranulation, superoxide anion generation, or survival, were examined.

Results

We identified PD1 as one of the main anti-inflammatory and proresolving molecules synthesized in human eosinophils. PD1, in nanomolar concentrations, suppressed the chemotaxis induced by CCL11/eotaxin-1 or 5-oxo-eicosatetraenoic acid and modulated the expression of the adhesion molecules CD11b and L-selectin, although it had no effects on the degranulation, superoxide anion generation, or survival of the eosinophils. Compared with the cells harvested from healthy subjects, we observed a prominent decrease in the biosynthesis of PD1 by eosinophils from patients with severe asthma, even in presence of DHA.

Conclusion

These observations are a first indication that activated human eosinophils represent a major source of PD1, which can act as a self-resolving machinery in eosinophilic inflammation, whereas the production of PD1 is impaired in patients with severe asthma.