The arachidonic acid metabolite 11,12-epoxyeicosatrienoic acid alleviates pulmonary fibrosis

Hak Su Kim,Gi Won Hwang,Jin Woo Song,Sang Eun Lee,Su-Jin Moon,Hyun Ju Yoo

doi:10.1038/s12276-021-00618-7

Abstract

Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid that are rapidly metabolized into diols by soluble epoxide hydrolase (sEH). sEH inhibition has been shown to increase the biological activity of EETs, which are known to have anti-inflammatory properties. However, the role of EETs in pulmonary fibrosis remains unexplored. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to analyze EETs in the lung tissues of patients with idiopathic pulmonary fibrosis (IPF, n = 29) and controls (n = 15), and the function of 11,12-EET was evaluated in in vitro and in vivo in pulmonary fibrosis models. EET levels in IPF lung tissues, including those of 8,9-EET, 11,12-EET, and 14,15-EET, were significantly lower than those in control tissues. The 11,12-EET/11,12-DHET ratio in human lung tissues also differentiated IPF from control tissues. 11,12-EET significantly decreased transforming growth factor (TGF)-β1-induced expression of α-smooth muscle actin (SMA) and collagen type-I in MRC-5 cells and primary fibroblasts from IPF patients. sEH-specific siRNA and 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU; sEH inhibitor) also decreased TGF-β1-induced expression of α-SMA and collagen type-I in fibroblasts. Moreover, 11,12-EET and TPPU decreased TGF-β1-induced p-Smad2/3 and extracellular-signal-regulated kinase (ERK) expression in primary fibroblasts from patients with IPF and fibronectin expression in Beas-2B cells. TPPU decreased the levels of hydroxyproline in the lungs of bleomycin-induced mice. 11,12-EET or sEH inhibitors could inhibit pulmonary fibrosis by regulating TGF-β1-induced profibrotic signaling, suggesting that 11,12-EET and the regulation of EETs could serve as potential therapeutic targets for IPF treatment.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrosing interstitial pneumonia of unknown etiology characterized by irreversible loss of lung function and poor prognosis[1]
Increased expression of soluble epoxide hydrolase (sEH) contributes to changes in Epoxyeicosatrienoic acids (EETs) levels in IPF lung tissues As EETs are rapidly metabolized into their corresponding diol forms by sEH, we measured the levels of dihydroxyeicosatrienoic acids (DHETs)
Our data suggest that the reduced levels of 11,12-EET in IPF lung tissues might be due to the upregulation of sEH

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrosing interstitial pneumonia of unknown etiology characterized by irreversible loss of lung function and poor prognosis[1]. The characteristic progressive fibrosis in IPF is due to fibroblast activation, which is regulated by various metabolic mediators, including lipid metabolites[3,4,5]. The metabolic mediators associated with the pathogenesis of IPF have not been fully identified. Eicosanoid metabolites of arachidonic acid play various roles in disease pathogenesis, such as anti-inflammatory, antifibrogenic and antiapoptotic roles[3,5,9,10]. Some eicosanoids, including prostaglandin E2, lipoxin A4, and prostacyclin, have shown antifibrotic effects on fibrosis models[3,11,12].

Methods

Results

Conclusion