Xu Jian, Wang Jingjing, Shao Chengjie, Zeng Xiaoning, Sun Lixiang, Kong Hui, Xie Weiping, Wang Hong
Department of Respiratory & Critical Care Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
J Thorac Dis. 2018 May;10(5):3016-3026. doi: 10.21037/jtd.2018.05.59.
In patients with pulmonary arterial hypertension (PAH), mast cells (MCs) are extensively observed around pulmonary vessels. However, their temporal and spatial variation during PAH development remains obscure. This study investigated the dynamic evolution of MCs in lungs and right ventricles (RV) to illuminate their role in pulmonary vascular and RV remodeling.
The PAH model was established by a single intra-peritoneal injection of monocrotaline (MCT, 60 mg/kg) in rats. On day 0, 3, 7, 14, and 28 after MCT injection, lung and RV tissues were harvested for staining with hematoxylin and eosin (HE), Gomori aldehyde fuchsin (GAF), toluidine blue (TB) and picrosirius red (PSR). Immunohistochemistry was performed to evaluate the levels of α-SMA, CD68 and tryptase. A simple RV remolding model was produced as well by pulmonary artery banding (PAB). RV tissues were collected to determine the degree of MCs infiltration.
After MCT challenge, elevated mean pulmonary arterial pressure (mPAP), increased RV systolic pressure (RVSP), pulmonary arterial media hypertrophy as well as distal vascular muscularization gradually occurred with time. MCs recruitment along with CD68+ macrophages accumulation was observed around distal pulmonary vessels and in alveolar septa. Excessive infiltration and degranulation of MCs were detected in MCT-treated group in lung tissues but not in RV. In addition, no exacerbation of MCs infiltration and degranulation in RV was noted in PAB-treated rats, suggesting few contributions of MCs to RV remodeling.
Our findings implied a crucial role of MCs in the remodeling of pulmonary vessels, not RV, which probably through releasing cytokines such as tryptase. The present study enriches the knowledge about PAH, providing a potential profile of MCs as a switch for the treatment of PAH.
在肺动脉高压（PAH）患者中，肺血管周围广泛观察到肥大细胞（MCs）。然而，它们在PAH发展过程中的时空变化仍不清楚。本研究调查了肺和右心室（RV）中MCs的动态演变，以阐明它们在肺血管和RV重塑中的作用。
通过单次腹腔注射野百合碱（MCT，60mg/kg）建立大鼠PAH模型。在注射MCT后的第0、3、7、14和28天，采集肺和RV组织，用苏木精和伊红（HE）、Gomori醛复红（GAF）、甲苯胺蓝（TB）和天狼星红（PSR）染色。进行免疫组织化学以评估α-SMA、CD68和类胰蛋白酶的水平。还通过肺动脉环扎（PAB）建立了一个简单的RV重塑模型。收集RV组织以确定MCs浸润程度。
MCT激发后，平均肺动脉压（mPAP）升高、RV收缩压（RVSP）增加、肺动脉中膜肥厚以及远端血管肌化随时间逐渐出现。在远端肺血管周围和肺泡间隔中观察到MCs募集以及CD68+巨噬细胞积聚。在MCT治疗组的肺组织中检测到MCs过度浸润和脱颗粒，但在RV中未检测到。此外，在PAB治疗的大鼠中未观察到RV中MCs浸润和脱颗粒的加重，表明MCs对RV重塑的贡献很小。
我们的研究结果表明MCs在肺血管而非RV重塑中起关键作用，这可能是通过释放类胰蛋白酶等细胞因子实现的。本研究丰富了关于PAH的知识，提供了MCs作为PAH治疗靶点的潜在概况。
