A Study of the Effect of an Interleukin-1 Receptor Antagonist on Pulmonary Vascular and Right Ventricular Remodeling in an Experimental Model of Chronic Thromboembolic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of pulmonary embolism characterized by a combination of mechanical obstruction and secondary microvasculopathy. Fibrotic remodeling and aseptic inflammation of the pulmonary artery vascular wall and perivascular space play a significant role in the progression of this disease. Interleukin (IL)-1 is one of the key pro-inflammatory cytokines; however, the effects of its blockade in CTEPH have been insufficiently studied. This study was aimed to evaluate the effect of an IL-1 receptor antagonist (anakinra) on pulmonary vascular and right ventricular (RV) remodeling in an experimental model of CTEPH. The study was performed on 64 Wistar rats. The CTEPH model was reproduced by repeated embolization of the distal pulmonary artery branches with partially biodegradable alginate microspheres. After modeling, the animals were divided into the following experimental groups: CTEPH control, Anakinra 10 mg/kg, and Anakinra 100 mg/kg. Healthy animals served as a comparison group. We assessed exercise tolerance, echocardiographic parameters, right ventricular systolic pressure (RVSP), histological vascular and RV remodeling, immunohistochemical markers of inflammation (CD68, CD3, CD20), and the levels of paracrine factors. In the CTEPH control group, we observed decreased exercise tolerance, increased RVSP, enhanced hypertrophic and fibrotic remodeling of the pulmonary artery, RV hypertrophy, increased CD68+, CD3+, and CD20+ infiltration, as well as elevated levels of CRP, MCP-1, MMP-9, and several other inflammatory mediators. Anakinra at both doses improved exercise tolerance, attenuated inflammatory manifestations of CTEPH, and dose-dependently limited pulmonary vascular and rV remodeling, especially at a dose 100 mg/kg. Meanwhile, no significant improvement in pulmonary hemodynamic parameters was obtained. The obtained data confirm the important role of IL-1-dependent inflammation in the pathogenesis of CTEPH and indicate the potential of IL-1 receptor blockade as a component of combination pathogenetic therapy.