Identification of 5-oxo-15-hydroxy-6,8,11,13-eicosatetraenoic acid as a novel and potent human eosinophil chemotactic eicosanoid.

Schwenk, Uwe; Morita, Eishin; Engel, Regina; Schröder, Jens‐Michael

doi:10.1016/s0021-9258(18)42302-2

Cited by 73 publications

(4 citation statements)

References 22 publications

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“…Expression of the receptor was detected on eosinophils, neutrophils, bronchoalveolar macrophages, basophils, monocytes, and a variety of cancer cell lines, with the highest expression on eosinophils [ 106 , 232 , 234 ]. Binding of 5-oxo-ETE to its receptor on eosinophils was reported to result in potent chemotaxis (highest among lipid mediators), increased cell activation, and degranulation [ 104 , 105 , 226 , 227 , 235 , 236 ]. Moreover, priming of eosinophils with granulocyte-macrophage colony-stimulating factor enhances 5-oxo-ETE-induced eosinophil degranulation [ 236 ].…”

Section: Eicosanoids and Eosinophilsmentioning

confidence: 99%

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

Knuplez

Sturm

Marsche

2021

IJMS

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Eosinophils are important effector cells involved in allergic inflammation. When stimulated, eosinophils release a variety of mediators initiating, propagating, and maintaining local inflammation. Both, the activity and concentration of secreted and cytosolic phospholipases (PLAs) are increased in allergic inflammation, promoting the cleavage of phospholipids and thus the production of reactive lipid mediators. Eosinophils express high levels of secreted phospholipase A2 compared to other leukocytes, indicating their direct involvement in the production of lipid mediators during allergic inflammation. On the other side, eosinophils have also been recognized as crucial mediators with regulatory and homeostatic roles in local immunity and repair. Thus, targeting the complex network of lipid mediators offer a unique opportunity to target the over-activation and ‘pro-inflammatory’ phenotype of eosinophils without compromising the survival and functions of tissue-resident and homeostatic eosinophils. Here we provide a comprehensive overview of the critical role of phospholipase-derived lipid mediators in modulating eosinophil activity in health and disease. We focus on lysophospholipids, polyunsaturated fatty acids, and eicosanoids with exciting new perspectives for future drug development.

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Section: Eicosanoids and Eosinophilsmentioning

confidence: 99%

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

Knuplez

Sturm

Marsche

2021

IJMS

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“…Although the eosinophil plays an important pathological role in many asthmatics, cysLTs have only very modest chemoattractant effects on these cells (Powell et al, 1995). Similarly, the potent neutrophil chemoattractant LTB 4 is only a very weak chemoattractant for human eosinophils (Powell et al, 1995; Schwenk et al, 1992; Sun et al, 1991), despite its potent effects on guinea pig eosinophils (Sun et al, 1991). In contrast, another 5‐LO product, 5‐oxo‐ETE (5‐oxo‐6,8,11,14‐eicosatetraenoic acid), is a potent chemoattractant for human eosinophils, both in vitro (Powell et al, 1995) and in vivo, following subcutaneous injection (Muro et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Targeting the OXE receptor with a selective antagonist inhibits allergen‐induced pulmonary inflammation in non‐human primates

Cossette

Miller

et al. 2021

British J Pharmacology

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Background and Purpose The 5‐lipoxygenase product, 5‐oxo‐ETE (5‐oxo‐6,8,11,14‐eicosatetraenoic acid), is a potent chemoattractant for eosinophils and neutrophils. However, little is known about its pathophysiological role because of the lack of a rodent ortholog of the oxoeicosanoid (OXE) receptor. The present study aimed to determine whether the selective OXE receptor antagonist S‐Y048 can inhibit allergen‐induced pulmonary inflammation in a monkey model of asthma. Experimental Approach Monkeys sensitized to house dust mite antigen (HDM) were treated with either vehicle or S‐Y048 prior to challenge with aerosolized HDM, and bronchoalveolar (BAL) fluid was collected 24 h later. After 6 weeks, animals that had initially been treated with vehicle received S‐Y048 and vice versa for animals initially treated with S‐Y048. Eosinophils and neutrophils in BAL and lung tissue samples were evaluated, as well as mucus‐containing cells in bronchi. Key Results HDM significantly increased the numbers of eosinophils, neutrophils, and macrophages in BAL fluid 24 h after challenge. These responses were all significantly inhibited by S‐Y048, which also reduced the numbers of eosinophils and neutrophils in lung tissue 24 h after challenge with HDM. S‐Y048 also significantly reduced the numbers of bronchial epithelial cells staining for mucin and MUC5AC after antigen challenge. Conclusion and Implications This study provides the first evidence that 5‐oxo‐ETE may play an important role in inducing allergen‐induced pulmonary inflammation and could also be involved in regulating MUC5AC in goblet cells. OXE receptor antagonists such as S‐Y048 may useful therapeutic agents in asthma and other eosinophilic as well as neutrophilic diseases.

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“…Somewhat to our surprise, 5-oxo-12-HETE and its 8- trans -isomer have virtually no biological activity on neutrophils. In contrast, another 5-oxo-HETE, namely 5-oxo-15-HETE, displays substantial activity on both neutrophils and eosinophils . 5-Oxo-12-HETE was more than 10,000 times less active than 5-oxo-ETE in mobilizing calcium in neutrophils, and preliminary experiments indicate that, in contrast to 5-oxo-ETE and 5-oxo-15-HETE, it does not induce neutrophil migration at concentrations as high as 10 μM .…”

Section: Resultsmentioning

confidence: 86%

“…In contrast, another 5-oxo-HETE, namely 5-oxo-15-HETE, displays substantial activity on both neutrophils 17 and eosinophils. 18 5-Oxo-12-HETE was more than 10,000 times less active than 5-oxo-ETE in mobilizing calcium in neutrophils, 16 and preliminary experiments indicate that, in contrast to 5-oxo-ETE and 5-oxo-15-HETE, it does not induce neutrophil migration at concentrations as high as 10 µM. 19 Comparison of the structures of 5-oxo-ETE (5), 5-oxo-15-HETE (32), and 5-oxo-12-HETE (6) (Scheme 6) suggests that a saturated carbon at position 10 is essential for biological activity mediated by the activation of the 5-oxo-ETE receptor.…”

Section: Resultsmentioning

confidence: 99%

The Total Synthesis of 5-Oxo-12(S)-hydroxy-6(E),8(Z),10(E),14(Z)-eicosatetraenoic Acid and Its 8,9-trans-Isomer and Their Identification in Human Platelets

1998

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Identification of 5-oxo-15-hydroxy-6,8,11,13-eicosatetraenoic acid as a novel and potent human eosinophil chemotactic eicosanoid.

Cited by 73 publications

References 22 publications

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

Targeting the OXE receptor with a selective antagonist inhibits allergen‐induced pulmonary inflammation in non‐human primates

The Total Synthesis of 5-Oxo-12(S)-hydroxy-6(E),8(Z),10(E),14(Z)-eicosatetraenoic Acid and Its 8,9-trans-Isomer and Their Identification in Human Platelets

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