Abstract Rationale In a recent Phase 2a trial, the selective oral angiotensin II type 2 receptor (AT2R) agonist buloxibutid stabilized and improved lung function in patients with idiopathic pulmonary fibrosis (IPF) over 36 weeks. Because vascular pathology is a driver of morbidity and mortality in pulmonary fibrosis, we investigated how buloxibutid affects pulmonary fibrosis as well as vascular remodeling in the rat Sugen-hypoxia (SuHx) model - an experimental system relevant to pulmonary arterial hypertension (PAH) and in several respects to pulmonary hypertension (PH) in interstitial lung disease (ILD). Methods Rats with established SuHx-induced pulmonary fibrosis and pulmonary hypertension received oral buloxibutid (2 or 20 mg/kg/day) for 3 weeks. Quantitative lung morphometry and AI-based histopathology was used to assess pulmonary fibrosis and vascular geometry. Results Buloxibutid reversed SuHx-induced pulmonary vascular remodeling, with both doses increasing the proportion of open (patent) resistance vessels from 45% to 54% in small (≤50 μm) arteries and from 68% to 77% in medium (50-100 μm) arteries (p 0.05 vs. vehicle). Moreover, buloxibutid significantly reduced muscular layer thickness by approximately 10% in vessels of both sizes (p 0.05). Buloxibutid tretment also reduced von Willebrand factor (vWF) area per vessel, a proxy for endothelial cell content, by approximately 25% compared to vechicle (p 0.001). A significant regression of pulmonary fibrosis was observed at the higher dose, evidenced by a 34% reduction in fibrotic area (p 0.05) and a 20% decrease in collagen content (p 0.001), indicating direct antifibrotic action in addition to the vascular effects. Vascular patency was inversely correlated with pulmonary fibrosis and collagen content (p 0.05), and lung collagen correlated positively with pulmonary artery pressures (p 0.05). Endothelial layer thickness correlated positively with resistance vessel patency (p 0.05) and inversely with muscularization (p 0.05). Conclusion Buloxibutid exhibited both vascular and antifibrotic benefits in the SuHx model of established PH and interstitial pulmonary fibrosis. Compressed and hyperplastic endothelium was partially normalized by treatment, indicating restoration of endothelial integrity. Lungs with more patent vessels and preserved endothelium were associated with less matrix accumulation, suggesting coordinated repair of the vascular and parenchymal compartments. This profile of distinct but interlinked reversal of vasculopathy and pulmonary fibrosis illustrates the potential of AT2R agonism in ILD and positions buloxibutid as a disease-modifying candidate for patients with PH-ILD and IPF. This abstract is funded by: Vicore Pharma AB
Raud et al. (Fri,) studied this question.