Targeting Plasminogen Activator Inhibitor-1 with a Novel Small Molecule Inhibitor Attenuates Lung Fibrosis

Abstract Fibrotic lung diseases are associated with significant morbidity and mortality, and few therapies have been FDA-approved for patients with these conditions. Therefore, developing effective anti-fibrotic treatments represents an unmet clinical need. Plasminogen activator inhibitor 1 (PAI-1) is an attractive therapeutic target as its expression is up-regulated in the context of fibrotic lung disease, and a causal role for PAI-1 in lung fibrogenesis has been established in complementary animal models. Here, we study the efficacy of a novel small molecule PAI-1 inhibitor, MDI-2517, to attenuate lung fibrosis. We observed that MDI-2517 administered during the fibrotic phase of complementary murine models reduces the severity of scarring. Furthermore, we found that MDI-2517 treatment beginning on day 21 after lung injury accelerates fibrosis resolution while in vitro data reveal that this drug reverses myofibroblast differentiation. These results motivate targeting PAI-1 as a therapy for lung fibrosis and highlight MDI-2517 as a promising drug.