Deng Yan, Guo Sheng-Lan, Wei Bin, Gao Xing-Cui, Zhou Ying-Chuan, Li Jia-Quan
Department of Ultrasound, The Cardiovascular Disease Institute, The First Affiliated Hospital to Guangxi Medical University, Nanning, China.
Department of Cardiology, The First Affiliated Hospital to Guangxi Medical University, Nanning, China.
Front Pharmacol. 2019 Feb 26;10:128. doi: 10.3389/fphar.2019.00128. eCollection 2019.
Inflammation and altered immunity contribute to the development of pulmonary arterial hypertension (PH). The alpha 7 nicotinic acetylcholine receptor (α7nAChR) possesses anti-inflammatory activities. The current study was performed to investigate the effects of a selective α7nAChR agonist, PNU-282987, on controlling a monocrotaline (MCT)-induced rat model of PH and explored the underlying mechanisms. Sprague-Dawley rats were injected with MCT and treated with PNU-282987 at the prevention (starting 1 week before MCT) and treatment (starting 2 weeks after MCT) settings. Four weeks after MCT injection, hemodynamic changes, right ventricular structure, and lung morphological features were assessed. Enzyme-linked immunosorbent assay, Western blot and RT-PCR were performed to assess levels of inflammatory cytokines and NLRP3 (Nod-like receptor family pyrin domain-containing 3) inflammasome pathway in the rat lung tissues. In addition, the lung macrophage line NR8383 was used to confirm the data. Monocrotaline injection produced PH in rats and downregulated α7nAChR mRNA and protein expression in rat lung tissues compared to sham controls. Pharmacological activation of α7nAChR by PNU-282987 therapy improved the rat survival rate, attenuated the development of PH as assessed by remodeling of pulmonary arterioles, reduced the right ventricular (RV) systolic pressure, and ameliorated the hypertrophy and fibrosis of the RV in rats with MCT-induced PH. The expression of TNF-α, IL-6, IL-1β, and IL-18 were downregulated in rat lung tissues, which implied that PNU-282987 therapy may help regulate inflammation. These protective effects involved the inhibition of the NLRP3 inflammasome. assays of cultured rat lung macrophages confirmed that the anti-inflammation effect of PNU-282987 therapy may contribute to the disturbance of NLRP3 inflammasome activation. Targeting α7nAChR with PNU-282987 could effectively prevent and treat PH with benefits for preventing ongoing inflammation in the lungs of rats with MCT-induced PH by inhibiting NLRP3 inflammasome activation.
炎症和免疫改变促成了肺动脉高压（PH）的发展。α7烟碱型乙酰胆碱受体（α7nAChR）具有抗炎活性。本研究旨在探讨选择性α7nAChR激动剂PNU-282987对控制野百合碱（MCT）诱导的大鼠PH模型的作用，并探索其潜在机制。将Sprague-Dawley大鼠注射MCT，并在预防（MCT注射前1周开始）和治疗（MCT注射后2周开始）阶段用PNU-282987进行治疗。MCT注射4周后，评估血流动力学变化、右心室结构和肺形态特征。采用酶联免疫吸附测定、蛋白质印迹法和逆转录-聚合酶链反应来评估大鼠肺组织中炎性细胞因子水平和NLRP3（含Nod样受体家族吡咯结构域）炎性小体途径。此外，使用肺巨噬细胞系NR8383来验证数据。与假手术对照组相比，注射野百合碱使大鼠产生了PH，并下调了大鼠肺组织中α7nAChR mRNA和蛋白质表达。通过PNU-282987治疗对α7nAChR进行药理激活可提高大鼠存活率，减轻通过肺小动脉重塑评估的PH发展，降低右心室（RV）收缩压，并改善MCT诱导的PH大鼠的RV肥大和纤维化。大鼠肺组织中TNF-α、IL-6、IL-1β和IL-18的表达下调，这表明PNU-282987治疗可能有助于调节炎症。这些保护作用涉及对NLRP3炎性小体的抑制。对培养的大鼠肺巨噬细胞的检测证实，PNU-282987治疗的抗炎作用可能有助于干扰NLRP3炎性小体的激活。用PNU-282987靶向α7nAChR可有效预防和治疗PH，通过抑制NLRP3炎性小体激活，对预防MCT诱导的PH大鼠肺部的持续炎症有益。
