The comparison of two pendrin inhibitors, YS-01 and PDSinh-C01, in lipopolysaccharide-induced acute lung injury

Acute respiratory distress syndrome (ARDS) is a life-threatening condition without specific treatments, relying on mechanical ventilation and supportive care. Excessive inflammation and increased vascular permeability drive ARDS pathogenesis, with Bacterial pneumonia being the most common cause. Pendrin is upregulated in inflammatory lung diseases, and previous studies have demonstrated that its inhibition reduces lung injury. To develop pendrin inhibitors as potential therapeutic agents for ARDS, it is essential to identify the most effective candidate with minimal side effects. In this study, we compared the efficacy of two pendrin inhibitors, YS-01 and PDSinh-C01, in an LPS-induced acute lung injury (ALI) model. Wild-type mice were treated with LPS (10 mg/kg) intranasally to induce lung injury. YS-01 (10 mg/kg) and PDSinh-C01 (10 mg/kg) were administered intraperitoneally before or after LPS exposure. Lung injury was assessed based on bronchoalveolar lavage fluid (BALF) cell counts, protein levels, cytology, pathology, and lung injury scores. Pro-inflammatory cytokines and pendrin mRNA levels were measured in lung lysates. Additionally, pendrin-mediated Cl⁻/SCN⁻ exchange activity and cell viability were analyzed following treatment with the two inhibitors. Pendrin expression was elevated in LPS-induced lung injury but reduced by both YS-01 and PDSinh-C01 treatment. Both inhibitors mitigated lung injury by decreasing BALF cell counts, protein levels, and pro-inflammatory cytokine production in pre- and post-treatment groups. The two inhibitors showed compound-specific patterns across in vivo endpoints, with YS-01 producing lower lung injury scores in the pre-treatment paradigm and PDSinh-C01 producing lower scores in the post-treatment paradigm. In vitro, YS-01 demonstrated greater inhibitory potency against pendrin-mediated Cl⁻/SCN⁻ exchange activity and a more favorable cell viability profile under the tested conditions. Both YS-01 and PDSinh-C01 were active in this LPS-induced ALI model. The two inhibitors showed timing-dependent differences in histologic outcomes in vivo, with YS-01 favored in pre-treatment and PDSinh-C01 favored in post-treatment. YS-01 demonstrated a clearer in vitro advantage, with greater pharmacologic potency and a more favorable cell viability profile, supporting its further preclinical evaluation as a candidate compound in inflammatory lung injury.