15-Hydroxyeicosatrienoic acid induces nasal congestion by changing vascular functions in mice

Noriko Ozaki; Naoaki Sakamoto; Daiki Horikami; Yuri Tachibana; Nanae Nagata; Koji Kobayashi; Yoshino Taira Arai; Masayoshi Sone; Kazuhiro Hirayama; Takahisa Murata

doi:10.1016/j.alit.2023.12.007

15-Hydroxyeicosatrienoic acid induces nasal congestion by changing vascular functions in mice

Allergol Int. 2024 Jan 28:S1323-8930(24)00002-9. doi: 10.1016/j.alit.2023.12.007. Online ahead of print.

Authors

Affiliations

¹ Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan; Veterinary Public Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
² Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
³ Food and Animal Systemics, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
⁴ Sone Clinic Shinjuku, Tokyo, Japan.
⁵ Veterinary Public Health, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
⁶ Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan; Food and Animal Systemics, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan; Veterinary Pharmacology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan. Electronic address: amurata@mail.ecc.u-tokyo.ac.jp.

PMID: 38286715
DOI: 10.1016/j.alit.2023.12.007

Abstract

Background: Nasal congestion in allergic rhinitis (AR) is caused by vascular hyperpermeability and vascular relaxation of the nasal mucosa. We previously detected high levels of a lipoxygenation metabolite of dihomogammalinolenic acid, 15-hydroxy-8Z,11Z,13E-eicosatrienoic acid (15-HETrE) in the nasal lavage fluid of AR model mice. Here, we investigated the effects of 15-HETrE on vascular functions associated with nasal congestion.

Methods: We measured 15-HETrE levels in the nasal lavage fluid of ovalbumin-induced AR model mice and nasal discharge of patients with AR. We also assessed nasal congestion and vascular relaxation in mice. Vascular contractility was investigated using isolated mouse aortas.

Results: Five ovalbumin challenges increased 15-HETrE levels in AR model mice. 15-HETrE was also detected in patients who exhibiting AR-related symptoms. Intranasal administration of 15-HETrE elicited dyspnea-related behavior and decreased the nasal cavity volume in mice. Miles assay and whole-mount immunostaining revealed that 15-HETrE administration caused vascular hyperpermeability and relaxation of the nasal mucosa. Intravital imaging demonstrated that 15-HETrE relaxed the ear vessels that were precontracted via thromboxane receptor stimulation. Moreover, 15-HETrE dilated the isolated mouse aortas, and this effect was attenuated by K⁺ channel inhibitors and prostaglandin D₂ (DP) and prostacyclin (IP) receptor antagonists. Additionally, vasodilatory effects of 15-HETrE were accompanied by an increase in intracellular cAMP levels.

Conclusions: Our results indicate that 15-HETrE, whose levels are elevated in the nasal cavity upon AR, can be a novel lipid mediator that exacerbates nasal congestion. Moreover, it can stimulate DP and IP receptors and downstream K⁺ channels to dilate the nasal mucosal vasculature.

Keywords: 15-hydroxyeicosatrienoic acid; Allergic rhinitis; Fatty acid; Nasal obstruction; Vasodilation.