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Substantial evidence supports the involvement of the renin-angiotensin system in pulmonary hypertension (PH), and the angiotensin II type 2 receptor (AT2R) is known to exert tissue protective actions. The effect of the selective AT2R agonist C21 (also known as Compound 21 or buloxibutid) was evaluated in the rat Sugen-hypoxia PH model. After a single injection of Sugen 5416 and hypoxia for 21 days, C21 (2 or 20 mg/kg) or vehicle was administered perorally twice daily from Day 21 to Day 55. On Day 56, hemodynamic assessments were performed, and lung and heart tissue were prepared for quantification of cardiac and vascular remodeling and fibrosis. Treatment with C21 20 mg/kg improved cardiac output and stroke volume and decreased right ventricular hypertrophy (all p < 0.05). Treatment with C21 2 mg/kg significantly decreased vessel wall and muscular layer thickness and increased the luminal opening in vessels >100 μm (all p < 0.05). There were no significant differences between the two C21 doses on any parameter, and post hoc analyses comparing the merged C21 groups with the vehicle group showed that C21 treatment reduced vascular remodeling (reduced endothelial proliferation and thickening of the vascular wall) in vessels of all sizes; moreover, the diastolic pulmonary artery pressure and right ventricular pressure were reduced along with reduction of right ventricular hypertrophy. Sugen 5416 and hypoxia increased pulmonary collagen deposition, which was counteracted by C21 20 mg/kg. In conclusion, the effects of C21 on vascular remodeling, hemodynamic alterations, and fibrosis suggest that AT2R agonists may have a role in Group 1 and 3 PH treatment. [ABSTRACT FROM AUTHOR]

Interstitial lung disease (ILD) encompasses a heterogeneous group of more than 200 conditions, of which primarily idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, hypersensitivity pneumonitis, ILD associated with autoimmune diseases and sarcoidosis may present a progressive fibrosing (PF) phenotype. Despite different aetiology and histopathological patterns, the PF-ILDs have similarities regarding disease mechanisms with self-sustaining fibrosis, which suggests that the diseases may share common pathogenetic pathways. Previous studies show an enhanced activation of serotonergic signaling in pulmonary fibrosis, and the serotonin (5-HT)2 receptors have been implicated to have important roles in observed profibrotic actions. Our research findings in support by others, demonstrate antifibrotic effects with 5-HT2B receptor antagonists, alleviating several key events common for the fibrotic diseases such as myofibroblast differentiation and connective tissue deposition. In this review, we will address the potential role of 5-HT and in particular the 5-HT2B receptors in three PF-ILDs: ILD associated with systemic sclerosis (SSc-ILD), ILD associated with rheumatoid arthritis (RA-ILD) and IPF. Highlighting the converging pathways in these diseases discloses the 5-HT2B receptor as a potential disease target for PF-ILDs, which today have an urgent unmet need for therapeutic strategies. [ABSTRACT FROM AUTHOR]

Interstitial lung disease (ILD) encompasses a heterogeneous group of more than 200 conditions, of which primarily idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, hypersensitivity pneumonitis, ILD associated with autoimmune diseases and sarcoidosis may present a progressive fibrosing (PF) phenotype. Despite different aetiology and histopathological patterns, the PF-ILDs have similarities regarding disease mechanisms with self-sustaining fibrosis, which suggests that the diseases may share common pathogenetic pathways. Previous studies show an enhanced activation of serotonergic signaling in pulmonary fibrosis, and the serotonin (5-HT) 2 receptors have been implicated to have important roles in observed profibrotic actions. Our research findings in support by others, demonstrate antifibrotic effects with 5-HT 2B receptor antagonists, alleviating several key events common for the fibrotic diseases such as myofibroblast differentiation and connective tissue deposition. In this review, we will address the potential role of 5-HT and in particular the 5-HT 2B receptors in three PF-ILDs: ILD associated with systemic sclerosis (SSc-ILD), ILD associated with rheumatoid arthritis (RA-ILD) and IPF. Highlighting the converging pathways in these diseases discloses the 5-HT 2B receptor as a potential disease target for PF-ILDs, which today have an urgent unmet need for therapeutic strategies.