Galectin-3 inhibition ameliorates alveolar epithelial cell pyroptosis in phosgene-induced acute lung injury

Phosgene is a type of poisonous gas that can cause acute lung injury (ALI) upon accidental exposure. Casualties still occur due to phosgene-induced acute lung injury (P-ALI) from accidents resulting from improper operations. The pathological mechanisms of P-ALI are still understudied. Thus, we performed scRNA-seq on cells isolated from all subpopulations of the BALF in P-ALI and found that Gal3 expression was significantly higher in the gas group than in the control group. Further analysis revealed a ligand-receptor correspondence between alveolar macrophages (AMs) and alveolar epithelial cells (AEC), with Gal3 playing a key role in this interaction. To confirm and elaborate on this discovery, we selected four time points during the previous week: sham (day 0), day 1, day 3, and day 7 in the P-ALI mouse model and found that Gal3 expression was significantly elevated in P-ALI, most abundantly expressed in AM cells. This was further confirmed with the use of a Gal3 inhibitor. The inhibition of Gal3 and elimination of AMs in mice both attenuated epithelial cell pyroptosis, as confirmed in in vitro experiments, and revealed the Gal3/caspase-8/GSDMD signaling pathway. These findings suggest that Galectin-3 inhibition can ameliorate AEC pyroptosis by inhibiting the Gal3/caspase-8/GSDMD signaling pathway, thus reducing alveolar damage in mice with P-ALI. This finding provides novel insights for improving treatment efficacy for P-ALI.