Carbenoxolone decreases monocrotaline-induced pulmonary inflammation and pulmonary arteriolar remodeling in rats by decreasing the expression of connexins in T lymphocytes
Carbenoxolone decreases monocrotaline-induced pulmonary inflammation and pulmonary arteriolar remodeling in rats by decreasing the expression of connexins in T lymphocytes
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Carbenoxolone 通过降低 T 淋巴细胞中连接蛋白的表达来减轻野百合碱诱导的大鼠肺部炎症和肺小动脉重塑
DOI：
10.3892/ijmm.2019.4406
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发表时间：
2020-01-01
影响因子：
5.4
通讯作者：
Ma，Ke-Tao
中科院分区：
文献类型：
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作者：
Zhang，Liang;Fan，Zhi-Ru;Ma，Ke-Tao
由T淋巴细胞介导的适应性免疫应答是肺部炎症发病机制中公认的因素。T淋巴细胞中各种连接蛋白（Cxs）表达的变化或连接蛋白介导的细胞通讯的破坏有助于炎症或组织重塑。本研究旨在探讨阻断Cxs在野百合碱（MCT）诱导的大鼠肺部炎症模型中的潜在治疗价值。甘珀酸（CBX）用于抑制连接蛋白介导的细胞通讯。通过腹膜内（i. p.）注射单剂量MCT（60 mg/kg）和CBX处理（20 µg/kg/天，i. p.）在MCT治疗28天后的第二天开始。溶剂处理的雄性Sprague-Dawley大鼠用作阴性对照。通过测定肺动脉血流加速时间和右心室肥厚指数（RVHI）评价MCT大鼠模型。观察肺组织病理学改变及肺小动脉重构情况。检测各组T淋巴细胞亚群比例、T淋巴细胞亚群中Cx40/Cx43的表达以及血浆和肺组织中细胞因子水平。使用CBX对Cx进行药理学抑制可通过降低MCT处理大鼠肺组织中的RVHI、肺动脉壁增厚、胶原沉积和促炎性细胞因子产生以及CD 3+和CD 4 + T细胞蓄积，减轻MCT诱导的右心室肥大、肺小动脉重塑、肺纤维化和炎性细胞浸润。此外，流式细胞术分析显示，CBX可以抑制MCT诱导的肺组织中CD 4+和CD 8 + T淋巴细胞中Cx40和Cx43的表达。本研究提供的证据表明，Cx的药理学抑制可能会减弱MCT诱导的肺小动脉重塑和肺部炎症反应，至少部分是通过降低Cx表达。这些结果突出了T淋巴细胞中Cxs在MCT诱导的肺部炎症反应中的关键作用，并且Cxs的靶向可能是治疗肺部炎症性疾病的潜在治疗方法。
The adaptive immune response mediated by T lymphocytes is a well-established factor in the pathogenesis of pulmonary inflammation. Changes in the expression of various connexins (Cxs) or disruption of connexin-mediated cellular communication in T lymphocytes contribute to inflammation or tissue remodeling. The aim of the present study was to investigate the potential therapeutic value of blocking Cxs in a monocrotaline (MCT)-induced pulmonary inflammation rat model. Carbenoxolone (CBX) was used to inhibit connexin-mediated cellular communication. An MCT rat model was established by intraperitoneal (i.p.) injection of a single dose of MCT (60 mg/kg), and CBX treatment (20 µg/kg/day, i.p.) was initiated on the day following MCT treatment for 28 days. Vehicle-treated male Sprague-Dawley rats were used as the negative control. The MCT rat model was evaluated by measuring the pulmonary artery flow acceleration time and right ventricular hypertrophy index (RVHI). Histopathological features of the lung tissues and pulmonary arteriolar remodeling were assessed. The proportions of T lymphocyte subtypes, Cx40/cx43 expression in the T cell subtypes and the cytokine levels in the plasma and the lung tissues were also analyzed. Pharmacological inhibition of Cxs using CBX attenuated MCT-induced right ventricular hypertrophy, pulmonary arteriolar remodeling, lung fibrosis and inflammatory cell infiltration by decreasing the RVHI, pulmonary arterial wall thickening, collagen deposition and pro-inflammatory cytokines production as well as CD3+ and CD4+ T cell accumulation in lung tissues of MCT-treated rats. Furthermore, flow cytometry analysis revealed that CBX may inhibit MCT-induced Cx40 and Cx43 expression in CD4+ and CD8+ T lymphocytes in lung tissues. The present study provides evidence that pharmacological inhibition of Cxs may attenuate MCT-induced pulmonary arteriolar remodeling and pulmonary inflammatory response, at least in part, by decreasing Cx expression. The results highlight the critical role of Cxs in T lymphocytes in the MCT-induced pulmonary inflammatory response and that targeting of Cxs may be a potential therapeutic method for treating pulmonary inflammatory diseases.