PAI-1 inhibition attenuates the inflammatory response in a murine model of sclerodermatous chronic graft-versus-host disease

Hematopoietic stem cell transplantation (HSCT) is a critical tool for managing malignant and defective disorders of hematopoiesis but is limited by graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) remains a leading cause of non-relapse morbidity and mortality following allogeneic HSCT. Due to its high immunoreactivity, the skin is most commonly affected in cGVHD, where it undergoes aberrant tissue repair and progressive fibrosis. Therapeutic options for sclerodermatous cGVHD are limited and disease progression drives long-term morbidity and functional impairment. Plasminogen Activator Inhibitor-1 (PAI-1) is a mediator of tissue remodeling and fibrosis, regulating extracellular matrix deposition and the migration of fibrogenic cell populations. In this study, we hypothesized that pharmacologic inhibition of PAI-1 may improve clinical and histopathological outcomes in a murine model of sclerodermatous cGVHD by reducing pro-fibrotic signaling. C57BL/6 mice were conditioned with total body irradiation followed by intravenous infusion of bone marrow cells and splenocytes of either syngeneic (C57BL/6) or allogeneic (LP/J) donors. Mice received oral PAI-1 inhibitor PAI-039 (10 mg/kg) or vehicle every other day from day +14 until day +56. Clinical signs of GVHD and survival were monitored throughout this duration. At day +56, tissues and serum were collected for downstream molecular analyses. PAI-039 treatment improved survival and clinical GVHD scores. Serum levels of pro-inflammatory cytokines IFN-gamma (P=0.006) and TNF-alpha (P=0.002) were significantly reduced in PAI-039 treated mice compared to controls, alongside decreased expression of IFN-gamma (P=0.04) in skin isolates. These findings indicate that PAI-1 inhibition may provide therapeutic benefit in the treatment of sclerodermatous cGVHD by disrupting pathogenic fibrotic signaling, warranting further investigation.