Mitochondrial dysfunction-associated alveolar epithelial senescence is involved in CdCl₂-induced COPD-like lung injury

An earlier study found that respiratory cadmium chloride (CdCl₂) exposure caused COPD-like lung injury. This study aimed to explore whether mitochondrial dysfunction-mediated alveolar epithelial senescence is involved in CdCl₂-induced COPD-like lung injury. Adult C57BL/6 mice were exposed to CdCl₂ (10 mg/L) aerosol for six months. Beta-galactosidase-positive cells, p21 and p16 were increased in CdCl₂-exposed mouse lungs. The in vitro experiments showed that γ-H₂AX was elevated in CdCl₂-exposed alveolar epithelial cells. The cGAS-STING pathway was activated in CdCl₂-exposed alveolar epithelial cells and mouse lungs. Cxcl1, Cxcl9, Il-10, Il-1β and Mmp2, several senescence-associated secretory phenotypes (SASP), were upregulated in CdCl₂-exposed alveolar epithelial cells. Mechanistically, CdCl₂ exposure caused SIRT3 reduction and mitochondrial dysfunction in mouse lungs and alveolar epithelial cells. The in vitro experiment found that Sirt3 overexpression attenuated CdCl₂-induced alveolar epithelial senescence and SASP. The in vivo experiments showed that Sirt3 gene knockout exacerbated CdCl₂-induced alveolar epithelial senescence, alveolar structure damage, airway inflammation and pulmonary function decline. NMN, an NAD⁺ precursor, attenuated CdCl₂-induced alveolar epithelial senescence and SASP in mouse lungs. Moreover, NMN supplementation prevented CdCl₂-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 CdCl₂-induced COPD-like lung injury.