Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and life-threatening complication of pulmonary embolism. As existing animal models of CTEPH do not fully recapitulate complex disease pathophysiology, we report a new rat model for CTEPH evoked by repetitive embolization of the distal pulmonary artery branches with partially biodegradable alginate microspheres (MSs). MSs (180 ± 28 μm) were intravenously administered eight times at 4-day intervals; control animals received saline. The validity of the model was confirmed using transthoracic echocardiography, exercise testing, catheterization of the right ventricle, and histological examination of the lung and heart. The animals in the CTEPH group demonstrated a stable increase in right ventricular systolic pressure (RVSP) and decreased exercise tolerance. Histopathological examination revealed advanced medial hypertrophy in the small pulmonary arteries associated with fibrosis. The diameter of the main pulmonary artery was significantly larger in the CTEPH group than in the control group. Marinobufagenin and endothelin-1 serum levels were significantly elevated in rats with CTEPH. In conclusion, repetitive administration of alginate MSs in rats resulted in CTEPH development characterized by specific lung vasculature remodeling, reduced exercise tolerance, and a persistent rise in RVSP. The developed model can be used for pre-clinical testing of promising drug candidates.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism with poor clinical outcomes. Therapeutic approaches to prevention of fibrotic remodeling of the pulmonary vascular bed in CTEPH are limited. In this work, we tested the hypothesis that Janus kinase 1/2 (JAK1/2) inhibition with ruxolitinib might prevent and attenuate CTEPH in a rat model. CTEPH was induced by repeated embolization of the pulmonary artery with partially biodegradable 180 ± 30 μm alginate microspheres. Two weeks after the last injection of microspheres, ruxolitinib was administered orally at doses of 0.86, 2.58, and 4.28 mg/kg per day for 4 weeks. Prednisolone (1.475 mg/kg, i.m.) was used as a reference drug. Ruxolitinib in all doses as well as prednisolone reduced pulmonary vascular wall hypertrophy. Ruxolitinib at a dose of 2.58 mg/kg and prednisolone reduced vascular wall fibrosis. Prednisolone treatment resulted in decreased right ventricular systolic pressure. Pulmonary vascular resistance was lower in the prednisolone and ruxolitinib (4.28 mg/kg) groups in comparison with the placebo group. The plasma level of brain natriuretic peptide was lower in groups receiving ruxolitinib at doses of 2.58 and 4.28 mg/kg versus placebo. This study demonstrated that JAK1/2 inhibitor ruxolitinib dose-dependently reduced pulmonary vascular remodeling, thereby preventing CTEPH formation in rats.
Introduction. Chronic thromboembolic pulmonary hypertension (CTEPH) is the most common complication of pulmonary thromboembolism (PE). Fibrous remodeling of the pulmonary circulation vessels against the background of CTEPH leads to an irreversible increase of the vessel wall stiffness and the ineffectiveness of CTEPH treatment. The involvement of Janus kinase (JAK) in the regulation of vascular wall and lung tissue inflammation and fibrosis allows for the possible effectiveness of JAK 1,2 inhibitors (iJAK) in the course of CTEPH. Purpose – to study the antifibrotic effect of iJAK for the prevention and treatment of CTEPH. Materials and methods. The study was conducted on male Wistar rats. Modeling of CTEPH was performed by sequential embolization of the vascular bed with partially biodegradable sodium alginate microspheres. 2 weeks after the last administration of the microspheres, low, medium and high doses of iJAK were initiated. To assess the effectiveness of the substance, the following tests were used: treadmill test, echocardiography, cardiac catheterization with right ventricular (RV) manometry, histological examination of the lungs. Results. Animals undergone vascular embolization demonstrated decreased exercise tolerance at all observation points compared to healthy animals. The placebo group, in contrast with the group getting treatment and iJAK, was found to have an increased mean RV pressure compared to healthy animals. There was an increase in mean RV pressure in the placebo group (15.5±7.7 mmHg) and in the low dose and iJAK group (13.4±6.4 mmHg) compared with healthy animals (9.4±2.2 mmHg). Vascular hypertrophy of the pulmonary artery branches was lower in group getting average dosages and iJAK compared with the placebo group (54.9±19.0 and 68.9±23.1 %, respectively). Thus, the suppression by iJAK of aseptic inflammation and following fibrosis leads to the decreasing of severity of pulmonary circulation remodeling in the experimental model of CTEPH. This approach can be used in the comprehensive bypass and prevention of CTEPH.
Background. The formation of a pseudarthrosis is one of the most severe complications of bone fractures. Pseudarthrosis occurs as a result of a disorder in the fracture union, has a poor prognosis and requires long-term treatment and repeated surgeries. A small number of representative pseudarthrosis models makes it difficult to conduct preclinical studies of promising pharmacological substances, bone replacement materials and surgical methods of treatment.The aim. To develop and to validate an experimental model of normotrophic pseudarthrosis of a rabbit’s tibia by creating diastasis between bone fragments, forming local vascularization disturbance and using unstable fixation.Materials and methods. The study was carried out on Soviet Chinchilla rabbits. The animals were divided into 2 groups: in experimental group, we formed tibial pseudarthrosis; in control group, we made a simple transverse tibial fracture. The pseudarthrosis was formed by segmental resection (5 mm) of the middle third of the tibia, bone fragments dilatation for 5 mm, removal of periosteum and bone marrow within 5 mm followed by daily destabilization of a fracture in an external fixation device. The duration of the experiment was 6 weeks. X-ray examination of the fracture area was carried out weekly, multi-layer spiral computed tomography (MSCT) and histological examinations were carried out at the end of the experiment.Results. The survival value in the experiment was 100 %. According to weekly X-ray examination, fracture union was registered only in the control group and occurred on average on the 22,8 ± 5,1 day, while the formation of pseudarthrosis was observed only in the experimental group, and radiographic signs of a pseudarthrosis were noted on average on the 33,6 ± 3,5 day. The formation of a pseudarthrosis by the end of the experiment was confirmed by MSCT and histological studies.Conclusions. The developed model of the normotrophic pseudarthrosis of a rabbit’s tibia can be used for experimental tests of various factors for stimulating reparative regeneration and methods for treatment of the pseudarthrosis.
Chronic thromboembolic pulmonary hypertension (CTEPH) develops in 1.5–2.0% of patients experiencing pulmonary embolism (PE) and is characterized by stable pulmonary artery obstruction, heart failure, and poor prognosis. Little is known about involvement of autonomic nervous system (ANS) in the mechanisms of CTEPH. This study was aimed at evaluation of the effect of vagal and sympathetic denervation, as well as stimulation of the parasympathetic nervous system, on the outcomes of CTEPH in rats. CTEPH was induced by multiple intravenous injections of alginate microspheres. Sympathetic and vagal denervation was performed using unilateral surgical ablation of the stellate ganglion and vagotomy, respectively. Stimulation of the parasympathetic nervous system was carried out by administering pyridostigmine. The effect of neuromodulatory effects was assessed in terms of hemodynamics, histology, and gene expression. The results demonstrated the key role of ANS in the development of CTEPH. Sympathetic denervation as well as parasympathetic stimulation resulted in attenuated pulmonary vascular remodeling. These salutary changes were associated with altered MMP2 and TIMP1 expression in the lung and decreased FGFb level in the blood. Unilateral vagotomy had no effect on physiological and morphological outcomes of the study. The data obtained contribute to the identification of new therapeutic targets for CTEPH treatment.
Pulmonary embolism (PE) is the third most common cardiovascular disease. It is still associated with high hospital mortality, as well as with the development of acute and chronic complications. Treatment and prevention of PE and its complications requires high-tech approaches aimed at improving the prognosis of patients. In this regard, experimental studies aimed at studying the pathogenesis, improving diagnostic methods and searching for new pharmacological substances for the prevention and treatment of PE are in demand from the point of view of clinical practice. Considering the current trends in preclinical research, experimental work on rodents — mice, rats, hamsters, as well as on medium-sized laboratory animals (rabbits) is becoming more and more common. The use of these animal species is ethically acceptable and economically viable. The choice of a specific type of animal and a method for modeling PE is primarily determined by the objectives of the study. This article provides an overview of the main approaches to modeling PE, as well as discusses the advantages and disadvantages of each method. Special attention is paid to the modeling of chronic thromboembolic pulmonary hypertension (CTEPH) as one of the most dangerous complications of PE. The work analyzed publications from 1978 to 2020, in which PE was simulated in rodents and medium laboratory animals.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.