Hiram Roddy, Rizcallah Edmond, Marouan Sofia, Sirois Chantal, Sirois Marco, Morin Caroline, Fortin Samuel, Rousseau Eric
Department of Pharmacology and Physiology, Université de Sherbrooke, Sherbrooke, Quebec, Canada;
Department of Pathology, Université de Sherbrooke, Sherbrooke, Quebec, Canada;
Am J Physiol Lung Cell Mol Physiol. 2015 Oct 15;309(8):L776-88. doi: 10.1152/ajplung.00177.2015. Epub 2015 Aug 28.
Pulmonary hypertension (PH) is a rare disease in which pathophysiology is characterized by an increase in proinflammatory mediators, chronic endothelial dysfunctions, and a high migration rate of smooth muscle cells (SMC). Over the course of the last decade, various treatments have been proposed to relax the pulmonary arteries, none of which have been effective in resolving PH. Our hypothesis is that artery-relaxing drugs are not the long-term solution, but rather the inhibition of tissue inflammation, which underlies human pulmonary artery (HPA) dysfunctions that lead to abnormal vasoconstriction. The goal of the present study was to assess the anti-inflammatory effects of resolvin E1 (RvE1) with concomitant effects on SMC migration and on HPA reactivity. The role and mode of action of RvE1 and its precursor, monoacylglyceride eicosapentaenoic acid were assessed on HPA under proinflammatory conditions, involving a combined pretreatment with 10 ng/ml TNF-α and 10 ng/ml IL-6. Our results show that TNF-α and IL-6 treatment induced hyperreactivity and Ca(2+) hypersensitivity in response to pharmaco-mechanical stimuli, including 80 mM KCl, 1 μM phorbol 12-13-dibutyrate, and 30 nM U-46619. Furthermore, the proinflammatory treatment increased the migration rate of SMC isolated from HPA. The phosphorylation level of regulatory contractile proteins (CPI-17, MYPT-1), and proinflammatory signaling pathways (c-Fos, c-Jun, NF-κB) were also significantly increased compared with control conditions. Conversely, 300 nM RvE1 was able to normalize all of the above abnormal events triggered by proinflammation. In conclusion, RvE1 can resolve human arterial hyperreactivity via the resolution of inflammatory markers.
肺动脉高压（PH）是一种罕见疾病，其病理生理学特征为促炎介质增加、慢性内皮功能障碍和平滑肌细胞（SMC）高迁移率。在过去十年中，人们提出了各种治疗方法来舒张肺动脉，但没有一种方法能有效解决肺动脉高压问题。我们的假设是，动脉舒张药物并非长期解决方案，而抑制组织炎症才是关键，因为组织炎症是导致人类肺动脉（HPA）功能障碍进而引起异常血管收缩的根本原因。本研究的目的是评估消退素E1（RvE1）的抗炎作用及其对SMC迁移和HPA反应性的伴随影响。在促炎条件下，采用10 ng/ml肿瘤坏死因子-α（TNF-α）和10 ng/ml白细胞介素-6（IL-6）联合预处理，评估RvE1及其前体单酰甘油二十碳五烯酸在HPA上的作用和作用模式。我们的结果表明，TNF-α和IL-6处理会导致对包括80 mM氯化钾、1 μM佛波酯12 - 13 - 二丁酸酯和30 nM U - 46619在内的药物机械刺激产生高反应性和钙离子超敏反应。此外，促炎处理增加了从HPA分离的SMC的迁移率。与对照条件相比，调节性收缩蛋白（CPI - 17、MYPT - 1）的磷酸化水平以及促炎信号通路（c - Fos、c - Jun、核因子κB）也显著增加。相反，300 nM RvE1能够使上述由促炎引发的所有异常事件恢复正常。总之，RvE1可通过消除炎症标志物来解决人类动脉高反应性问题。
