Inhibition of soluble epoxide hydrolase in mice exposed to tobacco smoke

Abstract

Patients with chronic obstructive pulmonary disease exhibit inflammation in the respiratory tract. Epoxyeicosatrienoic acids (EETs) possess promising anti‐inflammatory properties. Hence, stabilization of EETs through inhibition of the enzyme soluble epoxide hydrolase (sEH) by small molecule inhibitors (sEHI) was investigated in a murine model of short‐term tobacco smoke (TS) exposure. Wild‐type (WT), and sEH knock out (KO) mice were exposed to filtered air (FA) or TS for 9 hours. Bronchoalveolar lavage fluid samples underwent solid phase extraction followed by liquid chromatography coupled to tandem mass spectrometry to facilitate quantitation of EETs, and their corresponding diols (DHETs) derived from arachidonic acid, as well as linoleic acid epoxides (EpOMEs), and diols (DiHOMEs). The total number of infiltrated cells was decreased in TS exposed KO mice, as well as in sEHI‐treated WT mice, compared to non‐treated mice exposed to TS. Both the EET/DHET ratio, and the EpOME/DiHOME ratio were increased in TS‐exposed WT mice treated with sEHI, compared to non‐treated mice exposed to TS. The ratios were further increased in KO mice, both exposed to TS and FA. Our results suggest that inhibition of sEH stabilizes EETs and EpOMEs, with potential beneficial effects in TS exposed mice.TRDRP 16KT‐0037, NIEHS Grants ES02710, P42 ES04699, and the Swedish Research Councils VR, Formas, and Vinnova supported this work.