Reverse remodeling and anti-proliferative effects of seralutinib in PAH precision-cut lung slices and pulmonary artery smooth muscle cells

<bold>Background:</bold> Pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) involves abnormal muscularization of small pulmonary arteries. Seralutinib is a novel PDGFR/CSF1R/c-KIT kinase inhibitor, targeting pathways that drive pulmonary artery vascular remodeling. Use of precision-cut lung slices (PCLS) from patients with PAH provides an opportunity to directly investigate the potential reverse remodeling effects of seralutinib. Furthermore, study of pulmonary artery smooth muscle cells from patients with PAH (PAH PASMCs) allows investigation of the anti-proliferative effects of seralutinib in these phenotypically distinct cells. <bold>Methods:</bold> In PAH PCLS, seralutinib-induced changes in pulmonary artery muscularization (αSMA), vessel thickness (histomorphometry), and apoptosis (TUNEL) were evaluated (n=3). In PAH PASMCs, proliferation (BrdU assay), protein (pPDGFR, pERK, pSMAD1/5/8), and mRNA (BMPR2, ID1/2/3) levels were assessed. Statistical analysis used one-way ANOVA, Dunnett’s test. <bold>Results:</bold> Seralutinib, at clinically relevant concentrations, decreased pulmonary artery muscularization in PAH PCLS by 42.5% (p<0.01). Apoptosis was increased in seralutinib-treated PCLS, and there was a trend in decreasing vessel wall thickness. In PASMCs, seralutinib decreased PDGFBB-induced phosphorylation of PDGFRβ and ERK. Seralutinib dose-dependently decreased proliferation of PASMCs. This decrease was accompanied by increased BMPR2, increased pSMAD1/5/8, and induction of downstream (ID) mRNA. <bold>Conclusion:</bold> Seralutinib demonstrated reverse remodeling in PAH PCLS. Inhaled seralutinib is in phase 3 development for PAH (PROSERA; <ext-link>NCT05934526</ext-link>).