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

Abstract

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.

• Authors: Chantal Cossette, Lisa A Miller, Qiuji Ye, Shishir Chourey, Chintam Nagendra Reddy, Joshua Rokach, William S Powell
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 179 Issue 2 Pg. 322-336 (01 2022) ISSN: 1476-5381 [Electronic] England
• PMID: 34766334 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021 The British Pharmacological Society.

Chemical References

• Allergens
• Receptors, Eicosanoid

Topics

• Allergens
• Animals
• Asthma (drug therapy)
• Eosinophils
• Pneumonia (drug therapy, prevention & control)
• Primates
• Receptors, Eicosanoid