Lung tissue RNA sequencing shows dysregulation of the bronchial epithelium in a rat model of chronic thromboembolic pulmonary hypertension

Background. Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by severe vascular wall remodeling, impaired angiogenesis, and aseptic inflammation of the pulmonary artery branches. All these changes lead to right ventricular heart failure, which is the cause of death in patients with PAH. Vascular damage and right ventricular failure are considered the main cause of respiratory dysfunction in pulmonary hypertension. However, changes in the respiratory tract remain largely unnoticed. The aim of this study was to investigate changes in gene expression in the lung tissue of rats with PAH induced by monocrotaline administration. Materials and methods. Wistar male rats (n = 12) were used in the experiment. To simulate PAH, animals were subcutaneously injected with a monocrotaline solution (Sigma-A ldrich, USA) at a dosage of 60 mg/kg. Six weeks after administration of monocrotaline, studies were performed: right ventricular catheterization (RV), histological examination of bronchi and pulmonary arteries, genetic analysis. Results. Totally 298 differentially expressed genes (DEGs) were detected, including 107 with increased and 191 with decreased gene expression. The most pronounced dysregulation of biological processes in the cluster with increased DEG expression was associated with phagocytosis, regulation of the immune response, and cellular response to lipoproteins. In the decreased DEG expression cluster, processes associated with cilia, their movement, and assembly were predominantly represented, indicating a connection with the ciliated epithelium of the bronchi. To confirm this, a histological study of the bronchi was performed. The obtained results demonstrate significant changes in the morphology of bronchi with a diameter from 100 to 1000 μm: a significant increase in the bronchial wall thickness index (PAH — 46,0 [38,8; 54,1] %, healthy animals (Intact) — 29,7 [24,8; 36,0] %, p ˂ 0,001), the height of bronchial epithelium (PAH — 12,5 [11,0; 14,6] μm, Intact — 8,0 [7,2; 9,6] μm, p ˂ 0,001), as well as the number of epithelial cells per 50 μm of the analyzed bronchial wall (PAH — 11,5 [10,7; 13,2], Intact — 8,2 [7,7; 9,0], p ˂ 0,001). Conclusions. Thus, transcriptional profiling indicated remodeling processes not only of the pulmonary vessels, but also of the lower respiratory tract, which was confirmed by histological examination.