Pulmonary surfactant biogenesis blockage mediated polyhexamethylene guanidine disinfectant induced pulmonary fibrosis

The widespread use of disinfectants and inhalation exposure to aerosolized forms is closely associated with adverse health effects on the respiratory system and pulmonary fibrosis, but the mechanism remains unclear. Here, we investigated the time-course pulmonary fibrosis effects of polyhexamethylene guanidine (PHMG) disinfectant inhalation exposure and elucidated its underlying mechanism. Specifically, scRNA-seq analysis revealed an initial increase in epithelial cell numbers after 4 weeks of PHMG exposure during induced pulmonary fibrosis, followed by a subsequent decrease after 8 weeks of exposure. Mechanistically, PHMG disrupted autophagic flux leading to intracellular accumulation and blocked pulmonary surfactant biogenesis in alveolar type II epithelial (AT2) cells both in vitro and in vivo. Furthermore, intervention studies using metformin confirmed that autophagy dysfunction mediated the blockage of pulmonary surfactant biogenesis in AT2 cells, playing a pivotal role in PHMG-induced pulmonary fibrosis. Our elucidation of these toxicological mechanisms provides valuable insights into the pathogenesis of pulmonary fibrosis triggered by environmental PHMG exposure, thereby offering a promising therapeutic target for mitigating and treating PHMG-associated pulmonary fibrosis.