Mitochondrial dysfunction-associated alveolar epithelial senescence is involved in CdCl 2-induced COPD-like lung injury

An earlier study found that respiratory cadmium chloride (CdCl 2 ) exposure caused COPD-like lung injury. This study aimed to explore whether mitochondrial dysfunction-mediated alveolar epithelial senescence is involved in CdCl 2-induced COPD-like lung injury. Adult C57BL/6 mice were exposed to CdCl 2 (10 mg/L) aerosol for six months. Beta-galactosidase-positive cells, p21 and p16 were increased in CdCl 2-exposed mouse lungs. The in vitro experiments showed that gamma-H 2 AX was elevated in CdCl 2-exposed alveolar epithelial cells. The cGAS-STING pathway was activated in CdCl 2-exposed alveolar epithelial cells and mouse lungs. Cxcl1 , Cxcl9 , Il-10 , Il-1 beta and Mmp2, several senescence-associated secretory phenotypes (SASP), were upregulated in CdCl 2-exposed alveolar epithelial cells. Mechanistically, CdCl 2 exposure caused SIRT3 reduction and mitochondrial dysfunction in mouse lungs and alveolar epithelial cells. The in vitro experiment found that Sirt3 overexpression attenuated CdCl 2- induced alveolar epithelial senescence and SASP. The in vivo experiments showed that Sirt3 gene knockout exacerbated CdCl 2-induced alveolar epithelial senescence, alveolar structure damage, airway inflammation and pulmonary function decline. NMN, an NAD + precursor, attenuated CdCl 2-induced alveolar epithelial senescence and SASP in mouse lungs. Moreover, NMN supplementation prevented CdCl 2-induced COPD-like alveolar structure damage, epithelial-mesenchymal transition and pulmonary function decline. These results suggest that mitochondrial dysfunction-associated alveolar epithelial senescence is involved in CdCl 2-induced COPD-like lung injury.