PD05, a novel neutrophil elastase inhibitor, mitigates LPS-induced acute lung injury in a preclinical model

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by neutrophil-dominant inflammation, disruption of the alveolar-capillary barrier, and severe hypoxemia, with persistently high mortality in infection-associated etiologies, including severe COVID-19 pneumonia. Neutrophil elastase (NE) is a central mediator of lung tissue destruction and inflammatory amplification in these conditions. However, currently available NE inhibitors such as Sivelestat have shown limited clinical efficacy. Here we evaluated the therapeutic potential of PD-05, a novel NE inhibitor, in murine model of ALI. ALI was induced in female C57BL/6 mice using intratracheal LPS (1 mg/kg), followed by oral administration of PD-05 (5 mg/kg). PD-05 significantly attenuated NE activity and reduced neutrophilic infiltration in lung tissue. Mechanistically, PD-05 suppressed NF-κB activation and reduced pro-inflammatory cytokines (TNF-α, IL-6, and Kc) levels, while decreasing ICAM-1 expression, consistent with reduced leukocyte recruitment and improved barrier integrity. PD-05 increased heme oxygenase-1 (HO-1) expression and restored surfactant protein C levels. These molecular changes translated into significant structural and functional improvement, evidenced by reduced septal thickening, preserved alveolar architecture, decreased HIF-1α expression, attenuation of airway hyperresponsiveness, and improved lung mechanics. Histological analysis further confirmed reduced lung injury and improved epithelial integrity in PD-05-treated mice. Collectively, PD-05 exerts coordinated anti-inflammatory and barrier-protective effects in experimental ALI, underscoring its translational potential for ALI and ARDS.