Purpose: Cigarette smoke exposure combined with Klebsiella pneumoniae (KP) infection were used to establish the model of chronic obstructive pulmonary disease (COPD) in mice to investigate the mechanism of airway remodeling. Methods: Male BALB/c mice (n=96) were randomly divided into Control group, CS group, KP group and CS+KP group. The mice were exposed to CS, KP and CS+KP from week 1 to 8, and were sacrificed at week 4, 8, 16 and 24. Minute volume (MV), the validity of the enhanced Pause (Penh), mean linear intercept (MLI), mean alveolar number (MAN) and the changes of lung pathological structure were detected. The expression levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in lung tissue were detected by ELISA kit. Collagen deposition was observed by masson staining and immunohistochemistry. The α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1) expression in lung tissue were detected by immunofluorescence. Human bronchial epithelioid cells were stimulated by cigarette smoke (CS) and lipopolysaccharide (LPS). The expression levels of airway epithelial junction proteins, autophagy-related protein and mTOR signaling were detected. Results: Compared with the Control group, MV of mice in CS+KP group were significantly decreased from week 4 to 24 (P<0.05 or P<0.01), and Penh of mice in CS+KP group were significantly increased from 8 to 24 weeks (P<0.05 or P<0.01), MV were significantly decreased and Penh were significantly increased in CS group from 8 to 16 weeks (P<0.05 or P<0.01), MV were significantly decreased in CS group from 8 to 16 weeks. Compared with the Control group, MAN were significantly decreased and MLI were significantly increased in lung tissue of mice in CS+KP group from week 4 to 24 (P<0.05 or P<0.01). At the week 8, massive inflammatory cell infiltration, alveolar wall thickening, alveolar rupture and fusion, and airway wall thickening were observed in lung tissue of mice in CS+KP group from week 8 to 24. The expression levels of IL-1β and TNF-α in CS+KP group were significantly increased (P<0.05 or P<0.01) from week 4 to 24; massive inflammatory cell infiltration, alveolar wall thickened, alveolar rupture and fusion, and airway wall thickened were observed in the lung tissues of CS group and KP group from week 8 to 16. MAN was significantly decreased, MLI, IL-1β and TNF-α levels were significantly increased in the lung tissues of CS group and KP group from week 8 to 16 (P<0.05 or P<0.01). Col Ⅰ, col Ⅲ, α-SMA and TGF-β1 in lung tissue of mice in CS+KP group were significantly increased from week 8 to 16(P<0.01); col Ⅰ was significantly increased in CS group from week 8 to 16 (P<0.01); col Ⅰ were significantly increased in KP group from week 8 to 16 and col Ⅲ were significantly increased in KP group at 8th week (P<0.01). In addition, increase in E-cad and decrease in N-cad were observed in 16HBE cells induced by CS and LPS (P<0.05), LC3B and Beclin-1 expression were significantly decreased (P<0.05), the expressions of p-mTOR, p-P70-S6K, and p-4E-BP1 were significantly increased in 16HBE cells induced by CS and LPS (P<0.05 or P<0.01). Conclusion: Pulmonary function declined, pathological changes of lung tissue and airway remodeling in COPD mice induced by CS and KP appeared to occur early and last long, and its mechanism may be related to the activation of mTORC1 signaling pathway to inhibit autophagy.