Department of Anesthesiology, Beijing Anzhen Hospital, Capital Medical University-Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, PR China.
Department of Anesthesiology, The Fourth Hospital of Changsha; The Digestive Surgery Institute of Changsha, Changsha, PR China.
Eur J Pharmacol. 2018 Nov 15;839:1-11. doi: 10.1016/j.ejphar.2018.09.012. Epub 2018 Sep 7.
Penehyclidine hydrochloride (PHC) is a new anticholinergic agent that provides protective effects in experimental models of heart and brain ischaemia as well as reperfusion (I/R) injury. In this study, we tested the hypothesis that PHC can alleviate lung ischaemia-reperfusion injury and improve pulmonary and systemic function in rats. PHC was administered intravenously at various doses (d= 0.1, 0.3, 1, 3 mg/kg) to I/R rats. We used six indicators, including lung function, histologic examination, pulmonary oedema, oxidative stress, inflammatory responses, and apoptosis staining to quantify the pulmonary and systemic protective effects of PHC. Haematoxylin and eosin staining was used for pulmonary histologic examination. The expression of Toll-like receptor (TLR) 4, phospho-inhibitor of NF-κB (p-IκB) and nuclear factor-kappa B (NF-κB) was analysed using western blotting. ELISA was conducted to detect inflammatory mediators. Oxidative stress markers as well as myeloperoxidase (MPO) were determined using an assay kit. PHC preconditioning (with concentrations ranging from 0.3 mg/kg to 3 mg/kg 30 min before the onset of I/R) significantly reduced lung histopathological changes, down regulated TLR4, p-IκB and NF-κB expression, and decreased inflammatory mediators as well as the total number of leukocytes and neutrophils in bronchoalveolar lavage (BAL) fluid and plasma. The lung tissue contents of reactive oxygen species (ROS), malondialdehyde (MDA), and MPO as well as pulmonary oedema formation decreased, while SOD (superoxide dismutase) activity was significantly upregulated. PHC preconditioning (with concentrations ranging from 1 mg/kg to 3 mg/kg) significantly improved the lung function and attenuated the apoptotic rate. The probable mechanism for this finding is the inhibition of proinflammatory mediators via the suppression of reactive oxygen species production and the TLR4/NF-κB signalling pathway.
盐酸戊乙奎醚（PHC）是一种新型的抗胆碱能药物，在心脏和大脑缺血以及再灌注（I/R）损伤的实验模型中提供保护作用。在这项研究中，我们检验了这样一个假设，即 PHC 可以减轻肺缺血再灌注损伤并改善大鼠的肺和全身功能。将 PHC 以不同剂量（d=0.1、0.3、1、3mg/kg）静脉注射到 I/R 大鼠中。我们使用六个指标，包括肺功能、组织学检查、肺水肿、氧化应激、炎症反应和凋亡染色，来量化 PHC 对肺和全身的保护作用。苏木精和伊红染色用于肺组织学检查。使用 Western 印迹分析 Toll 样受体（TLR）4、磷酸化核因子-kappa B（NF-κB）抑制物（p-IκB）和 NF-κB 的表达。酶联免疫吸附试验（ELISA）用于检测炎症介质。氧化应激标志物以及髓过氧化物酶（MPO）使用试剂盒测定。PHC 预处理（在 I/R 开始前 30 分钟用 0.3mg/kg 至 3mg/kg 的浓度）可显著减轻肺组织学变化，下调 TLR4、p-IκB 和 NF-κB 的表达，并降低炎症介质以及支气管肺泡灌洗液（BAL）和血浆中的白细胞和中性粒细胞总数。肺组织中活性氧（ROS）、丙二醛（MDA）和 MPO 的含量以及肺水肿形成减少，而 SOD（超氧化物歧化酶）活性显著上调。PHC 预处理（1mg/kg 至 3mg/kg 的浓度）可显著改善肺功能并降低细胞凋亡率。这种作用的可能机制是通过抑制活性氧的产生和 TLR4/NF-κB 信号通路来抑制促炎介质。
