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

<bold>Background:</bold> ARDS and ALI present significant clinical challenges with limited treatment options beyond mechanical ventilation and supportive care. Pendrin's role in their pathogenesis suggests therapeutic potential. This study aims to compare the efficacy of two pendrin inhibitors, YS-01 and PDS_inh-C01, in an LPS-induced ALI mouse model. <bold>Methods:</bold> LPS (10mg/kg) was intranasally administered to wild-type mice. YS-01 (10mg/kg) and PDSinh-C01 (10mg/kg) were delivered intraperitoneally before or aftter LPS exposure respectively. Lung injury parameters were assessed in lung tissue and bronchoalveolar lavage fluid (BALF), along with measurement of pro-inflammatory cytokines in lung lysates. Pendrin expression in Human Pulmonary Alveolar Epithelial Cells (HPAEpiC) was also evaluated. <bold>Results:</bold> Pendrin expression increased in LPS-induced lung injury mice but decreased with pre-treatment and post-treatment of YS-01 and PDS_inh-CO1. Both inhibitors attenuated lung injury, reducing cell counts and protein concentration in BALF. Additionally, they decreased pro-inflammatory cytokine levels in LPS-induced ALI. Pendrin expression in HPAEpiC was upregulated by LPS exposure and downregulated by YS-01 and PDS_inh-C01 pre-treatment. YS-01 exhibited superior inhibitory effects on pendrin-mediated Cl_-/SCN_- exchange activity and cell viability compared to PDS_inh-C01. <bold>Conclusions:</bold> The findings suggest that YS-01 and PDS_inh-C01 offer promising therapeutic strategies for inflammatory airway diseases, including ALI. Particularly, YS-01 demonstrates potential as a more effective therapeutic agent for ALI compared to PDS_inh-C01.