Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Capital Medical University, Beijing, China.
Department of Physiology and Pathophysiology, School of BasicMedical Sciences, Capital Medical University, Beijing, China.
Thorax. 2019 Jun;74(6):564-578. doi: 10.1136/thoraxjnl-2018-211846. Epub 2019 Feb 18.
The role of interleukin 17 (IL-17) in hypoxic pulmonary hypertension (HPH) remains unclear. This study is designed to explore whether IL-17 is a potential target for HPH treatment.
Clinic samples from the lung tissue and serum were obtained from qualified patients. Western blotting, immunohistochemistry and/or ELISA were used to measure the expression of relevant proteins. HPH models were established in C57BL/6 wild-type (WT) and mice and were treated with exogenous recombinant mouse IL-17 (rmIL-17) or an IL-17 neutralising antibody. Assays for cell proliferation, angiogenesis and adhesion were employed to analyse the behaviours of human pulmonary arterial endothelial cells (HPAECs). A non-contact Transwell coculture model was used to evaluate intercellular interactions.
Expression of IL-17 was increased in lung tissue of both patients with bronchiectasis/COPD-associated PH and HPH mouse model. Compared with WT mice, mice had attenuated HPH, whereas administration of rmIL-17 aggravated HPH. In vitro, recombinant human IL-17 (rhIL-17) promoted proliferation, angiogenesis and adhesion in HPAECs through upregulation of Wnt3a/β-catenin/CyclinD1 pathway, and siRNA-mediated knockdown of β-catenin almost completely reversed this IL-17-mediated phenomena. IL-17 promoted the proliferation but not the migration of human pulmonary arterial smooth muscle cells (HPASMCs) cocultured with HPAECs under both normoxia and hypoxia, but IL-17 had no direct effect on proliferation and migration of HPASMCs. Blockade of IL-17 with a neutralising antibody attenuated HPH in WT mice.
IL-17 contributes to the pathogenesis of HPH through upregulation of β-catenin expression. Targeting IL-17 might provide potential benefits for alternative therapeutic strategies for HPH.
白细胞介素 17（IL-17）在低氧性肺动脉高压（HPH）中的作用尚不清楚。本研究旨在探讨 IL-17 是否是 HPH 治疗的潜在靶点。
从合格患者的肺组织和血清中获取临床样本。采用 Western blot、免疫组织化学和/或 ELISA 检测相关蛋白的表达。在 C57BL/6 野生型（WT）和 小鼠中建立 HPH 模型，并给予外源性重组鼠 IL-17（rmIL-17）或 IL-17 中和抗体进行治疗。采用细胞增殖、血管生成和黏附测定分析人肺动脉内皮细胞（HPAEC）的行为。采用非接触 Transwell 共培养模型评估细胞间相互作用。
支气管扩张/COPD 相关 PH 和 HPH 小鼠模型的肺组织中 IL-17 的表达增加。与 WT 小鼠相比， 小鼠的 HPH 减轻，而给予 rmIL-17 则加重了 HPH。在体外，重组人 IL-17（rhIL-17）通过上调 Wnt3a/β-catenin/CyclinD1 通路促进 HPAEC 的增殖、血管生成和黏附，而用 siRNA 介导的β-catenin 敲低几乎完全逆转了这种由 IL-17 介导的现象。IL-17 促进了在常氧和低氧条件下与 HPAEC 共培养的人肺动脉平滑肌细胞（HPASMC）的增殖，但不促进其迁移，但 IL-17 对 HPASMC 的增殖和迁移没有直接影响。用中和抗体阻断 IL-17 减轻了 WT 小鼠的 HPH。
IL-17 通过上调 β-catenin 的表达促进 HPH 的发病机制。靶向 IL-17 可能为 HPH 的替代治疗策略提供潜在的益处。
