Development of a clinically relevant rat model of chronic thromboembolic pulmonary hypertension by combining splenectomy with pulmonary thromboembolism.

Abstract

BACKGROUND: 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 CD79AB 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.