Reproducible lung protective effects of a TGFβR1/ALK5 inhibitor in the bleomycin-induced and spirometry-confirmed mouse model of IPF

<bold>Aims and objectives:</bold> Reliability of reference drug effects is critical when probing novel antifibrotic drug therapies in preclinical models of idiopathic pulmonary fibrosis (IPF). Here, we compared the therapeutic effects of a TGFβR1/ALK5 inhibitor (ALK5i) in four independent studies in the bleomycin (BLEO)-induced and spirometry-confirmed mouse model of IPF. <bold>Methods:</bold> 12-week-old male C57BL/6JRj mice received a single intratracheal instillation of BLEO (2.0 mg/kg) or saline (CTRL). Seven days after BLEO administration, animals were randomized into study groups based on whole-body plethysmography (PenH) and body weight, followed by 21 days of oral ALK5i treatment (SB525334, 30 mg/kg, BID). Terminal pulmonary endpoints included spirometry, hydroxyproline (HP), Ashcroft score, quantitative histological markers of fibrogenesis (α-SMA) and fibrosis (PSR, Col1a1, Col3). <bold>Results:</bold> BLEO-IPF mice developed functional, histological, and biochemical hallmarks of IPF, characterized by a significant decline in expiratory and inspiratory capacity with progressive fibrotic development. In all 4 studies, Alk5i significantly improved lung function (FEV0.1, FVC, inspiratory capacity, static compliance), reflected by reduced levels of biochemical (HP) and histological (PSR) markers of lung fibrosis. <bold>Conclusions:</bold> ALK5i reproducibly improves pulmonary function and lung fibrosis in the BLEO-IPF mouse, supporting the use of Alk5i as an active comparator in the model.