Inhibition of allergen‐induced dermal eosinophilia by an oxoeicosanoid receptor antagonist in non‐human primates. (17th January 2020)

• Record Type: Journal Article
• Authors: Miller, Lisa A.; Cossette, Chantal; Chourey, Shishir; Ye, Qiuji; Reddy, Chintam Nagendra; Rokach, Joshua; Powell, William S.
• Is Part Of: British journal of pharmacology. Volume 177:Number 2(2020)
• Page Start: 360
• Page End: 371
• Publication Date: 2020-01-17
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.14872
• Languages: English
• ISSNs: 0007-1188

Abstract

Abstract : Background and Purpose: 5‐Oxo‐6, 8, 11, 14‐eicosatetraenoic acid (5‐oxo‐ETE), acting via the OXE receptor, is unique among 5‐lipoxygenase products in its ability to directly induce human eosinophil migration, suggesting its involvement in eosinophilic diseases. To address this hypothesis, we synthesized selective indole‐based OXE receptor antagonists. Because rodents lack an OXE receptor orthologue, we sought to determine whether these antagonists could attenuate allergen‐induced skin eosinophilia in sensitized monkeys. Experimental Approach: In a pilot study, cynomolgus monkeys with environmentally acquired sensitivity to Ascaris suum were treated orally with the "first‐generation" OXE antagonist 230 prior to intradermal injection of 5‐oxo‐ETE or Ascaris extract. Eosinophils were evaluated in punch biopsy samples taken 6 or 24 hr later. We subsequently treated captive‐bred rhesus monkeys sensitized to house dust mite (HDM) allergen with a more recently developed OXE antagonist, S ‐Y048, and evaluated its effects on dermal eosinophilia induced by either 5‐oxo‐ETE or HDM. Key Results: In a pilot experiment, both 5‐oxo‐ETE and Ascaris extract induced dermal eosinophilia in cynomolgus monkeys, which appeared to be reduced by 230 . Subsequently, we found that the related OXE antagonist S ‐Y048 is a highly potent inhibitor of 5‐oxo‐ETE‐induced activation of rhesus monkey eosinophils in vitro and has a half‐life in plasma of about 6 hr after oral administration. S ‐Y048 significantly inhibited eosinophil infiltration into the skin in response to both intradermally administered 5‐oxo‐ETE and HDM. Conclusions and Implications: 5‐Oxo‐ETE may play an important role in allergen‐induced eosinophilia. Blocking its effects with S ‐Y048 may provide a novel therapeutic approach for eosinophilic diseases.