State Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Dept of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
These authors contributed equally to this manuscript.
Eur Respir J. 2023 Mar 2;61(3). doi: 10.1183/13993003.00582-2022. Print 2023 Mar.
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.
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 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.
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.
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 14/17-HDHA.
肺动脉高压（PH）是一种危及生命的疾病，其特征是肺血管重塑和血管周围炎症。嗜酸性粒细胞（EOS）对 PH 发展的影响尚不清楚。
研究了无过敏史的肺动脉高压（PAH）患者和 SuGEN/低氧诱导的 PH 小鼠的外周血和肺组织中 EOS 的浸润和趋化作用。利用缺失（ΔdblGATA）小鼠和抗白细胞介素 5 抗体治疗的小鼠和大鼠研究了 EOS 缺乏在 PH 发展中的作用。采用超高效液相色谱-串联质谱（UHPLC-MS/MS）鉴定 EOS 产生的关键氧化脂分子。在共培养细胞实验中，收集培养上清液和 EOS 裂解物以探索机制。
PAH 患者和 PH 小鼠的外周血中 EOS 百分比较低，但肺组织中浸润较多。PAH/PH 肺组织中 EOS 相关趋化因子表达增加，主要来自外膜成纤维细胞的 C-C 基序趋化因子配体 11。EOS 缺乏加重了啮齿动物的 PH，同时伴有中性粒细胞和单核细胞/巨噬细胞浸润增加。EOS 高度表达花生四烯酸 15-脂氧合酶（ALOX15）。14-羟基二十二碳六烯酸（14-HDHA）和 17-HDHA 是 EOS 产生的关键下游氧化脂，通过 N-甲酰肽受体 2 对中性粒细胞和单核细胞/巨噬细胞的募集显示出抗炎作用。它们还通过激活过氧化物酶体增殖物激活受体 γ 和抑制 Stat3 磷酸化来抑制肺动脉平滑肌细胞（PASMC）增殖。
在没有外部刺激的 PH 发展过程中，外周血表现出低 EOS 水平。EOS 通过抑制血管周围炎症和维持 PASMC 稳态发挥保护作用，14/17-HDHA。
