The arachidonic acid metabolite 11,12-epoxyeicosatrienoic acid alleviates pulmonary fibrosis.
Hak Su KimSu-Jin MoonSang Eun LeeGi Won HwangHyun Ju YooJin Woo SongPublished in: Experimental & molecular medicine (2021)
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.
Keyphrases
- pulmonary fibrosis
- idiopathic pulmonary fibrosis
- transforming growth factor
- poor prognosis
- diabetic rats
- high glucose
- tandem mass spectrometry
- gene expression
- liquid chromatography
- epithelial mesenchymal transition
- smooth muscle
- drug induced
- mass spectrometry
- transcription factor
- high performance liquid chromatography
- binding protein
- chronic kidney disease
- oxidative stress
- end stage renal disease
- induced apoptosis
- signaling pathway
- ultra high performance liquid chromatography
- extracellular matrix
- cell death
- ms ms
- ejection fraction
- long non coding rna
- skeletal muscle
- endoplasmic reticulum stress
- climate change
- cancer therapy
- replacement therapy
- combination therapy