12-OH-17,18-Epoxyeicosatetraenoic acid alleviates eosinophilic airway inflammation in murine lungs

Takao Mochimaru, Koichi Fukunaga, J. Miyata, Masako Matsusaka, Katsunori Masaki, Hiroki Kabata, Soichiro Ueda, Y. Suzuki, T. Goto, D. Urabe, M. Inoue, Y. Isobe, Makoto Arita, Tomoko Betsuyaku

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: Asthma is characterized by airway inflammation and obstruction with eosinophil infiltration into the airway. Arachidonic acid, an omega-6 fatty acid, is metabolized into cysteinyl leukotriene with pro-inflammatory properties for allergic inflammation, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) and its downstream metabolites are known to have anti-inflammatory effects. In this study, we investigated the mechanism underlying the counter-regulatory roles of EPA in inflamed lungs. Methods: Male C57BL6 mice were sensitized and challenged by ovalbumin (OVA). After EPA treatment, we evaluated the cell count of Bronchoalveolar lavage fluid (BALF), mRNA expressions in the lungs by q-PCR, and the amounts of lipid mediators by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics. We investigated the effect of the metabolite of EPA by in vivo and in vitro studies. Results: Eicosapentaenoic acid treatment reduced the accumulation of eosinophils in the airway and decreased mRNA expression of selected inflammatory mediators in the lung. Lipidomics clarified the metabolomic profile in the lungs. Among EPA-derived metabolites, 12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE) was identified as one of the major biosynthesized molecules; the production of this molecule was amplified by EPA administration and allergic inflammation. Intravenous administration of 12-OH-17,18-EpETE attenuated airway eosinophilic inflammation through downregulation of C-C chemokine motif 11 (CCL11) mRNA expression in the lungs. In vitro, this molecule also inhibited the release of CCL11 from human airway epithelial cells stimulated with interleukin-4. Conclusion: These results demonstrated that EPA alleviated airway eosinophilic inflammation through its conversion into bioactive metabolites. Additionally, our results suggest that 12-OH-17,18-EpETE is a potential therapeutic target for the management of asthma.

Original languageEnglish
JournalAllergy: European Journal of Allergy and Clinical Immunology
DOIs
Publication statusAccepted/In press - 2017

Fingerprint

Eicosapentaenoic Acid
Inflammation
Lung
Acids
Eosinophils
Messenger RNA
Asthma
Omega-6 Fatty Acids
CC Chemokines
Metabolomics
hydroxide ion
Ovalbumin
Bronchoalveolar Lavage Fluid
Omega-3 Fatty Acids
Airway Obstruction
Tandem Mass Spectrometry
Arachidonic Acid
Liquid Chromatography
Interleukin-4
Intravenous Administration

Keywords

  • Asthma
  • Lipidomics
  • Omega-3 fatty acid
  • Specialized pro-resolving mediator

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

12-OH-17,18-Epoxyeicosatetraenoic acid alleviates eosinophilic airway inflammation in murine lungs. / Mochimaru, Takao; Fukunaga, Koichi; Miyata, J.; Matsusaka, Masako; Masaki, Katsunori; Kabata, Hiroki; Ueda, Soichiro; Suzuki, Y.; Goto, T.; Urabe, D.; Inoue, M.; Isobe, Y.; Arita, Makoto; Betsuyaku, Tomoko.

In: Allergy: European Journal of Allergy and Clinical Immunology, 2017.

Research output: Contribution to journalArticle

Mochimaru, Takao ; Fukunaga, Koichi ; Miyata, J. ; Matsusaka, Masako ; Masaki, Katsunori ; Kabata, Hiroki ; Ueda, Soichiro ; Suzuki, Y. ; Goto, T. ; Urabe, D. ; Inoue, M. ; Isobe, Y. ; Arita, Makoto ; Betsuyaku, Tomoko. / 12-OH-17,18-Epoxyeicosatetraenoic acid alleviates eosinophilic airway inflammation in murine lungs. In: Allergy: European Journal of Allergy and Clinical Immunology. 2017.
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abstract = "Background: Asthma is characterized by airway inflammation and obstruction with eosinophil infiltration into the airway. Arachidonic acid, an omega-6 fatty acid, is metabolized into cysteinyl leukotriene with pro-inflammatory properties for allergic inflammation, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) and its downstream metabolites are known to have anti-inflammatory effects. In this study, we investigated the mechanism underlying the counter-regulatory roles of EPA in inflamed lungs. Methods: Male C57BL6 mice were sensitized and challenged by ovalbumin (OVA). After EPA treatment, we evaluated the cell count of Bronchoalveolar lavage fluid (BALF), mRNA expressions in the lungs by q-PCR, and the amounts of lipid mediators by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics. We investigated the effect of the metabolite of EPA by in vivo and in vitro studies. Results: Eicosapentaenoic acid treatment reduced the accumulation of eosinophils in the airway and decreased mRNA expression of selected inflammatory mediators in the lung. Lipidomics clarified the metabolomic profile in the lungs. Among EPA-derived metabolites, 12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE) was identified as one of the major biosynthesized molecules; the production of this molecule was amplified by EPA administration and allergic inflammation. Intravenous administration of 12-OH-17,18-EpETE attenuated airway eosinophilic inflammation through downregulation of C-C chemokine motif 11 (CCL11) mRNA expression in the lungs. In vitro, this molecule also inhibited the release of CCL11 from human airway epithelial cells stimulated with interleukin-4. Conclusion: These results demonstrated that EPA alleviated airway eosinophilic inflammation through its conversion into bioactive metabolites. Additionally, our results suggest that 12-OH-17,18-EpETE is a potential therapeutic target for the management of asthma.",
keywords = "Asthma, Lipidomics, Omega-3 fatty acid, Specialized pro-resolving mediator",
author = "Takao Mochimaru and Koichi Fukunaga and J. Miyata and Masako Matsusaka and Katsunori Masaki and Hiroki Kabata and Soichiro Ueda and Y. Suzuki and T. Goto and D. Urabe and M. Inoue and Y. Isobe and Makoto Arita and Tomoko Betsuyaku",
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T1 - 12-OH-17,18-Epoxyeicosatetraenoic acid alleviates eosinophilic airway inflammation in murine lungs

AU - Mochimaru, Takao

AU - Fukunaga, Koichi

AU - Miyata, J.

AU - Matsusaka, Masako

AU - Masaki, Katsunori

AU - Kabata, Hiroki

AU - Ueda, Soichiro

AU - Suzuki, Y.

AU - Goto, T.

AU - Urabe, D.

AU - Inoue, M.

AU - Isobe, Y.

AU - Arita, Makoto

AU - Betsuyaku, Tomoko

PY - 2017

Y1 - 2017

N2 - Background: Asthma is characterized by airway inflammation and obstruction with eosinophil infiltration into the airway. Arachidonic acid, an omega-6 fatty acid, is metabolized into cysteinyl leukotriene with pro-inflammatory properties for allergic inflammation, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) and its downstream metabolites are known to have anti-inflammatory effects. In this study, we investigated the mechanism underlying the counter-regulatory roles of EPA in inflamed lungs. Methods: Male C57BL6 mice were sensitized and challenged by ovalbumin (OVA). After EPA treatment, we evaluated the cell count of Bronchoalveolar lavage fluid (BALF), mRNA expressions in the lungs by q-PCR, and the amounts of lipid mediators by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics. We investigated the effect of the metabolite of EPA by in vivo and in vitro studies. Results: Eicosapentaenoic acid treatment reduced the accumulation of eosinophils in the airway and decreased mRNA expression of selected inflammatory mediators in the lung. Lipidomics clarified the metabolomic profile in the lungs. Among EPA-derived metabolites, 12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE) was identified as one of the major biosynthesized molecules; the production of this molecule was amplified by EPA administration and allergic inflammation. Intravenous administration of 12-OH-17,18-EpETE attenuated airway eosinophilic inflammation through downregulation of C-C chemokine motif 11 (CCL11) mRNA expression in the lungs. In vitro, this molecule also inhibited the release of CCL11 from human airway epithelial cells stimulated with interleukin-4. Conclusion: These results demonstrated that EPA alleviated airway eosinophilic inflammation through its conversion into bioactive metabolites. Additionally, our results suggest that 12-OH-17,18-EpETE is a potential therapeutic target for the management of asthma.

AB - Background: Asthma is characterized by airway inflammation and obstruction with eosinophil infiltration into the airway. Arachidonic acid, an omega-6 fatty acid, is metabolized into cysteinyl leukotriene with pro-inflammatory properties for allergic inflammation, whereas the omega-3 fatty acid eicosapentaenoic acid (EPA) and its downstream metabolites are known to have anti-inflammatory effects. In this study, we investigated the mechanism underlying the counter-regulatory roles of EPA in inflamed lungs. Methods: Male C57BL6 mice were sensitized and challenged by ovalbumin (OVA). After EPA treatment, we evaluated the cell count of Bronchoalveolar lavage fluid (BALF), mRNA expressions in the lungs by q-PCR, and the amounts of lipid mediators by liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based lipidomics. We investigated the effect of the metabolite of EPA by in vivo and in vitro studies. Results: Eicosapentaenoic acid treatment reduced the accumulation of eosinophils in the airway and decreased mRNA expression of selected inflammatory mediators in the lung. Lipidomics clarified the metabolomic profile in the lungs. Among EPA-derived metabolites, 12-hydroxy-17,18-epoxyeicosatetraenoic acid (12-OH-17,18-EpETE) was identified as one of the major biosynthesized molecules; the production of this molecule was amplified by EPA administration and allergic inflammation. Intravenous administration of 12-OH-17,18-EpETE attenuated airway eosinophilic inflammation through downregulation of C-C chemokine motif 11 (CCL11) mRNA expression in the lungs. In vitro, this molecule also inhibited the release of CCL11 from human airway epithelial cells stimulated with interleukin-4. Conclusion: These results demonstrated that EPA alleviated airway eosinophilic inflammation through its conversion into bioactive metabolites. Additionally, our results suggest that 12-OH-17,18-EpETE is a potential therapeutic target for the management of asthma.

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KW - Lipidomics

KW - Omega-3 fatty acid

KW - Specialized pro-resolving mediator

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