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Abstract <p>Chronic thromboembolic pulmonary hypertension (CTEPH) is acomplication of pulmonary embolism characterized by a combinationof mechanical obstruction and secondary microvasculopathy. Fibroticremodeling and aseptic inflammation of the pulmonary artery vascularwall and perivascular space play a significant role in the progressionof this disease. Interleukin (IL)-1 is one of the key pro-inflammatorycytokines; however, the effects of its blockade in CTEPH have beeninsufficiently studied. This study was aimed to evaluate the effectof an IL-1 receptor antagonist (anakinra) on pulmonary vascularand right ventricular (RV) remodeling in an experimental model ofCTEPH. The study was performed on 64 Wistar rats. The CTEPH modelwas reproduced by repeated embolization of the distal pulmonaryartery branches with partially biodegradable alginate microspheres.After modeling, the animals were divided into the following experimentalgroups: CTEPH control, Anakinra 10 mg/kg, and Anakinra 100 mg/kg.Healthy animals served as a comparison group. We assessed exercisetolerance, echocardiographic parameters, right ventricular systolicpressure (RVSP), histological vascular and RV remodeling, immunohistochemicalmarkers of inflammation (CD68, CD3, CD20), and the levels of paracrinefactors. In the CTEPH control group, we observed decreased exercisetolerance, increased RVSP, enhanced hypertrophic and fibrotic remodelingof the pulmonary artery, RV hypertrophy, increased CD68+, CD3+, andCD20+ infiltration, as well as elevated levels of CRP, MCP-1, MMP-9,and several other inflammatory mediators. Anakinra at both dosesimproved exercise tolerance, attenuated inflammatory manifestationsof CTEPH, and dose-dependently limited pulmonary vascular and rVremodeling, especially at a dose 100 mg/kg. Meanwhile, no significant improvementin pulmonary hemodynamic parameters was obtained. The obtained dataconfirm the important role of IL-1-dependent inflammation in thepathogenesis of CTEPH and indicate the potential of IL-1 receptorblockade as a component of combination pathogenetic therapy.</p>

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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

  • 期刊论文

  • 发表日期：

    2026年6月21日

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  • A. A. Karpov,
  • V. V. Karpenko,
  • D. D. Vaulina,
  • A. V. Vorotilov,
  • E. V. Semenova,
  • N. P. Isakova,
  • S. S. Smirnov,
  • M. A. Simakova,
  • Yu. I. Karpova,
  • E. S. Alekseeva,
  • S. G. Chefu,
  • D. Yu. Ivkin,
  • M. M. Galagudza

摘要

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is acomplication of pulmonary embolism characterized by a combinationof mechanical obstruction and secondary microvasculopathy. Fibroticremodeling and aseptic inflammation of the pulmonary artery vascularwall and perivascular space play a significant role in the progressionof this disease. Interleukin (IL)-1 is one of the key pro-inflammatorycytokines; however, the effects of its blockade in CTEPH have beeninsufficiently studied. This study was aimed to evaluate the effectof an IL-1 receptor antagonist (anakinra) on pulmonary vascularand right ventricular (RV) remodeling in an experimental model ofCTEPH. The study was performed on 64 Wistar rats. The CTEPH modelwas reproduced by repeated embolization of the distal pulmonaryartery branches with partially biodegradable alginate microspheres.After modeling, the animals were divided into the following experimentalgroups: CTEPH control, Anakinra 10 mg/kg, and Anakinra 100 mg/kg.Healthy animals served as a comparison group. We assessed exercisetolerance, echocardiographic parameters, right ventricular systolicpressure (RVSP), histological vascular and RV remodeling, immunohistochemicalmarkers of inflammation (CD68, CD3, CD20), and the levels of paracrinefactors. In the CTEPH control group, we observed decreased exercisetolerance, increased RVSP, enhanced hypertrophic and fibrotic remodelingof the pulmonary artery, RV hypertrophy, increased CD68+, CD3+, andCD20+ infiltration, as well as elevated levels of CRP, MCP-1, MMP-9,and several other inflammatory mediators. Anakinra at both dosesimproved exercise tolerance, attenuated inflammatory manifestationsof CTEPH, and dose-dependently limited pulmonary vascular and rVremodeling, especially at a dose 100 mg/kg. Meanwhile, no significant improvementin pulmonary hemodynamic parameters was obtained. The obtained dataconfirm the important role of IL-1-dependent inflammation in thepathogenesis of CTEPH and indicate the potential of IL-1 receptorblockade as a component of combination pathogenetic therapy.