Dados do Trabalho

Título

REVERSE REMODELING AND ANTI-PROLIFERATIVE EFFECTS OF SERALUTINIB IN PAH PRECISION-CUT LUNG SLICES AND PULMONARY ARTERY SMOOTH MUSCLE CELLS

Introdução

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.

Objetivo

To directly investigate the potential reverse remodeling effects of seralutinib using precision-cut lung slices (PCLS) from patients with PAH. Furthermore, the 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.

Método

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.

Resultados

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.

Conclusão

Seralutinib demonstrated reverse remodeling in PAH PCLS. Inhaled seralutinib is in phase 3 development for PAH (PROSERA; NCT05934526).