Eosinophils protect against pulmonary hypertension through 14-HDHA and 17-HDHA. Issue 3 (2nd March 2023)

• Record Type: Journal Article
• Authors: Shu, Ting; Zhang, Jiawei; Zhou, Yitian; Chen, Zhihua; Li, Jinqiu; Tang, Qihao; Lei, Wenqi; Xing, Yanjiang; Wang, Jing; Wang, Chen
• Is Part Of: European respiratory journal. Volume 61:Issue 3(2023)
• Publication Date: 2023-03-02
• Subjects: Respiratory organs -- Diseases -- Periodicals; Respiration -- Periodicals; 616.2
• DOI: 10.1183/13993003.00582-2022
• Languages: English
• ISSNs: 0903-1936

Abstract

Background: Pulmonary hypertension (PH) is a life-threatening disease featuring pulmonary vessel remodelling and perivascular inflammation. The effect, if any, of eosinophils (EOS) on the development of PH remains unclear. Methods: EOS infiltration and chemotaxis were investigated in peripheral blood and lung tissues from pulmonary arterial hypertension (PAH) patients without allergic history and from sugen/hypoxia-induced PH mice. The role of EOS deficiency in PH development was investigated using GATA1- deletion (ΔdblGATA) mice and anti-interleukin 5 antibody-treated mice and rats. Ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was conducted to identify the critical oxylipin molecule(s) produced by EOS. Culture supernatants and lysates of EOS were collected to explore the mechanisms in co-culture cell experiments. Results: There was a lower percentage of EOS in peripheral blood but higher infiltration in lung tissues from PAH patients and PH mice. PAH/PH lungs showed increased EOS-related chemokine expression, mainly C-C motif chemokine ligand 11 derived from adventitial fibroblasts. EOS deficiency aggravated PH in rodents, accompanied by increased neutrophil and monocyte/macrophage infiltration. EOS highly expressed arachidonate 15-lipoxygenase (ALOX15). 14-hydroxy docosahexaenoic acid (14-HDHA) and 17-HDHA were critical downstream oxylipins produced by EOS, which showed anti-inflammatory effects on recruitment of neutrophils and monocytes/macrophages through N-formyl peptide receptor 2. They also repressed pulmonary artery smooth muscle cell (PASMC) proliferation by activating peroxisome proliferator-activated receptor γ and blunting Stat3 phosphorylation. Conclusions: In PH development without external stimuli, peripheral blood exhibits a low EOS level. EOS play a protective role by suppressing perivascular inflammation and maintaining PASMC homeostasis via 14/17-HDHA. EOS infiltrate lung tissues of PAH patients and PH mice. EOS deficiency aggravates PH development. EOS-derived 14-HDHA and 17-HDHA suppress inflammation through FPR2 and maintain pulmonary arterial smooth muscle cell homeostasis through PPARγ. https://bit.ly/3fjqGN3