Development of a clinically relevant rat model of chronic thromboembolic pulmonary hypertension by combining splenectomy with pulmonary thromboembolism
Haobing Zhang a), Xiaoxuan Lu a), Zhuangjie Guo a), Xuehan Jiang a), Wensi Zhang a), Shuang Wang b), Qiwei Liu a), Xiaotong Dong a), Yishan Li c), Lina Guo a), Yu Zhang d), Jixiang Liu d), Zhu Zhang d), Wanmu Xie d), Wanlu Song a), Hong Zhang a), Zhenguo Zhai d), Peiran Yang a)
a) State Key Laboratory of Respiratory Health and Multimorbidity, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
b) School of Basic Medicine, Inner Mongolia Medical University, Inner Mongolia, Hohhot 010000, China
c) The First Clinical Medical College, Shanxi Medical University, Taiyuan, China
d) National Center for Respiratory Medicine, State Key Laboratory of Respiratory Health and Multimorbidity, National Clinical Research Center for Respiratory Diseases, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing 100029, China
Abstract
Introduction
Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe condition resulting from unresolved thrombi in the pulmonary arteries, leading to increased pulmonary vascular resistance and right heart failure. Currently, the scarcity of clinically relevant animal models of CTEPH significantly hampers mechanistic studies and drug development.
Methods
This study aimed to establish a rat model of CTEPH by combining splenectomy with thrombus injection, simulating key clinical risk factors associated with the disease. Rats underwent splenectomy and subsequent intravenous administration of thrombi, followed by hemodynamic and histological measurements as well as lung tissue RNA sequencing.
Results
Splenectomized rats exhibited significant increases in platelets and delayed thrombolysis. Five weeks after splenectomy and thrombus injection, the rats exhibited thrombus retention in large pulmonary arteries, increased right ventricular systolic pressure, and pulmonary vascular remodeling, which were characteristic of CTEPH. Transcriptomic analysis revealed increased expression of inflammatory cytokines Ccl2 and Ccl3, as well as the B cell marker Cd79a, which was confirmed as an increase in CD79A+ B cells in the lung tissue.
Conclusions
Overall, this novel approach of combining splenectomy with thrombus injection provides a clinically relevant model for studying CTEPH pathophysiology and evaluating potential therapeutic interventions.