Inhibition of JAK1,2 Prevents Fibrotic Remodeling of Pulmonary Vascular Bed and Improves Outcomes in the Rat Model of Chronic Thromboembolic Pulmonary Hypertension

Abstract

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.

Sympathetic Denervation and Pharmacological Stimulation of Parasympathetic Nervous System Prevent Pulmonary Vascular Bed Remodeling in Rat Model of Chronic Thromboembolic Pulmonary Hypertension

“…Unilateral vagotomy had no effect on physiological and morphological outcomes of the study. In this study, we used rat CTEPH model based on repetitive intravenous administration of partially biodegradable alginate microspheres [ 26 , 27 ]. In this model, progressive increase in embolic load followed by aseptic inflammation of vascular wall and activated fibrotic signaling results in a typical pattern of pulmonary vascular remodeling associated with residual microvascular obstruction.…”

“…All MSs were produced in sterile conditions. 50 μL of MSs by volume were suspended in 1 mL of 0.9% NaCl solution and administered via the tail vein 8 times separated by 4-day intervals [ 26 , 27 ]. Ten rats received injections of 0.9% NaCl solution instead of MSs suspension, thus forming the group of intact animals (INT).…”

Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

“…In preclinical trials and preclinical genetic studies, ruxolitinib was found to exhibit potential cardiotoxicity that may present as toxic myocardial damage, decreased left ventricular systolic function, or cardiac failure. [472][473][474] The selective JAK1 and JAK2 inhibitor baricitinib was approved for the treatment of RA in 2017 and has been widely confirmed to improve clinical symptoms of RA in patients that have an inadequate response to methotrexate. 475,476 The RA-BEAM trial involving patients with moderately to severely active RA and an inadequate response to methotrexate showed that baricitinib was superior to placebo with respect to signs and symptoms, physical function, and joint structural damage.…”