Study of the JAK inhibitors antifibrotic activity for the prevention and treatment of chronic thromboembolic pulmonary hypertension
https://doi.org/10.24884/1682-6655-2022-21-3-72-81
Abstract
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.
Keywords
pulmonary embolism,
chronic thromboembolic pulmonary hypertension,
sodium alginate,
microspheres,
experimental model,
rat,
CTEPH,
fibrous remodeling,
Janus kinase
Supporting agencies: The study was financially supported by state task No. 122041800020-2.
About the Authors
A. A. Karpov
Almazov National Medical Research Centre; Saint Petersburg State Chemical Pharmaceutical University
Russian Federation
Russian Federation
Karpov Andrei A. – PhD, MD, Chief of the Laboratory of Pulmonary Vascular Disease
2, Akkuratova str., Saint Petersburg, 197341
14, Professor Popov str. 14, Saint Petersburg, 197376
D. D. Vaulina
Almazov National Medical Research Centre
Russian Federation
Russian Federation
Vaulina Dariya D. – Junior researcher of the Laboratory of Pulmonary Vascular Disease
2, Akkuratova str., Saint Petersburg, 197341
A. M. Mikhailova
Almazov National Medical Research Centre
Russian Federation
Russian Federation
Mikhailova Alexandra M. – Junior researcher of the Laboratory of Pulmonary Vascular Disease
2, Akkuratova str., Saint Petersburg, 197341
S. S. Smirnov
Almazov National Medical Research Centre; Pavlov University
Russian Federation
Russian Federation
Smirnov Sergey S. – research laboratory assistant of the Laboratory of Pulmonary Vascular Disease; clinical resident 1 year of study
2, Akkuratova str., Saint Petersburg, 197341
6-8, L’va Tolstogo street, Saint Petersburg, 197022
L. A. Shilenko
Almazov National Medical Research Centre; Pavlov University
Russian Federation
Russian Federation
Shilenko Leonid A. – research laboratory assistant of the Laboratory of Pulmonary Vascular Disease; student
2, Akkuratova str., Saint Petersburg, 197341
6-8, L’va Tolstogo street, Saint Petersburg, 197022
N. A. Anikin
Almazov National Medical Research Centre
Russian Federation
Russian Federation
Anikin Nikita A. – Junior researcher of the Laboratory of Pulmonary Vascular Disease
2, Akkuratova str., Saint Petersburg, 197341
Z. I. Chepurnoy
Almazov National Medical Research Centre; Pavlov University
Russian Federation
Russian Federation
Chepurnoy Zakhar I. – research laboratory assistant of the Laboratory of Pulmonary Vascular Disease; student
2, Akkuratova str., Saint Petersburg, 197341
6-8, L’va Tolstogo street, Saint Petersburg, 197022
A. V. Vorotilov
Almazov National Medical Research Centre
Russian Federation
Russian Federation
Vorotilov Alexander V. – clinical resident 1 year of study
2, Akkuratova str., Saint Petersburg, 197341
A. G. Stafeeva
Almazov National Medical Research Centre
Russian Federation
Russian Federation
Stafeeva Anna G. – student
2, Akkuratova str., Saint Petersburg, 197341
N. S. Bunenkov
Almazov National Medical Research Centre; Pavlov University
Russian Federation
Russian Federation
Bunenkov Nikolay S. – PhD, MD, doctor; Junior researcher of the Laboratory of Pulmonary Vascular Disease
2, Akkuratova str., Saint Petersburg, 197341
6-8, L’va Tolstogo street, Saint Petersburg, 197022
D. Yu. Ivkin
Saint Petersburg State Chemical Pharmaceutical University
Russian Federation
Russian Federation
Ivkin Dmitry Y. – PhD, Director of the Center for Experimental Pharmacology
14, Professor Popov str. 14, Saint Petersburg, 197376
M. M. Galagudza
Almazov National Medical Research Centre; Pavlov University
Russian Federation
Russian Federation
Galagudza Michael M. – MD, Dr. Med. Sci., Professor and Corresponding Member of the Russian Academy of Science, Director of the Institute of Experimental Medicine; Professor at the Department of Pathophysiology
2, Akkuratova str., Saint Petersburg, 197341
6-8, L’va Tolstogo street, Saint Petersburg, 197022
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Review
For citations:
Karpov A.A., Vaulina D.D., Mikhailova A.M., Smirnov S.S., Shilenko L.A., Anikin N.A., Chepurnoy Z.I., Vorotilov A.V., Stafeeva A.G., Bunenkov N.S., Ivkin D.Yu., Galagudza M.M. Study of the JAK inhibitors antifibrotic activity for the prevention and treatment of chronic thromboembolic pulmonary hypertension. Regional blood circulation and microcirculation. 2022;21(3):72-81. (In Russ.) https://doi.org/10.24884/1682-6655-2022-21-3-72-81
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