Sharma Ravindra K, Oliveira Aline C, Yang Tao, Kim Seungbum, Zubcevic Jasenka, Aquino Victor, Lobaton Gilberto O, Goel Ruby, Richards Elaine M, Raizada Mohan K
Dept of Physiology and Functional Genomics, University of Florida, Gainesville, FL, USA.
Dept of Physiology and Pharmacology, University of Toledo, Toledo, OH, USA.
ERJ Open Res. 2020 Jul 27;6(3). doi: 10.1183/23120541.00253-2019. eCollection 2020 Jul.
Emerging evidence implicates an interplay among multiple organs such as brain, vasculature, gut and lung in the development of established pulmonary arterial hypertension (PAH). This has led us to propose that activated microglia mediated-enhanced sympathetic activation contributes to PAH pathophysiology. Since enhanced sympathetic activity is observed in human PAH and the gut is highly innervated by sympathetic nerves that regulate its physiological functions, we hypothesized that PAH would be associated with gut pathophysiology. A monocrotaline rat model of PAH was utilized to investigate the link between gut pathology and PAH. Haemodynamics, histology, immunocytochemistry and 16S RNA gene sequencing were used to assess cardiopulmonary functions, gut pathology and gut microbial communities respectively. Monocrotaline treatment caused increased right ventricular systolic pressure, haemodynamics and pathological changes associated with PAH. PAH animals also showed profound gut pathology that included increased intestinal permeability, increased muscularis layer, decreased villi length and goblet cells. These changes in gut pathology were associated with alterations in microbial communities, some unique to PAH animals. Furthermore, enhanced gut-neural communication involving the paraventricular nucleus of the hypothalamus and increased sympathetic drive were observed. In conclusion, our data show the presence of gut pathology and distinct changes in gut microbiota and increased sympathetic activity in PAH. They suggest that dysfunctional gut-brain crosstalk could be critical in PAH and considered a future therapeutic target for PAH.
新出现的证据表明，在已确诊的肺动脉高压（PAH）的发展过程中，大脑、血管、肠道和肺等多个器官之间存在相互作用。这使我们提出，活化的小胶质细胞介导的交感神经激活增强促成了PAH的病理生理过程。由于在人类PAH中观察到交感神经活动增强，且肠道受调节其生理功能的交感神经高度支配，我们推测PAH可能与肠道病理生理有关。利用野百合碱诱导的大鼠PAH模型来研究肠道病理与PAH之间的联系。分别采用血流动力学、组织学、免疫细胞化学和16S RNA基因测序来评估心肺功能、肠道病理和肠道微生物群落。野百合碱处理导致右心室收缩压升高、血流动力学改变以及与PAH相关的病理变化。PAH动物还表现出严重的肠道病理改变，包括肠道通透性增加、肌层增厚、绒毛长度和杯状细胞减少。这些肠道病理变化与微生物群落的改变有关，其中一些是PAH动物特有的。此外，还观察到涉及下丘脑室旁核的肠道神经通讯增强以及交感神经驱动增加。总之，我们的数据表明PAH存在肠道病理、肠道微生物群的明显变化以及交感神经活动增加。这些结果提示，功能失调的肠-脑相互作用可能在PAH中起关键作用，并可被视为PAH未来的治疗靶点。
