Objective To compare differences in chronic obstructive pulmonary disease (COPD) models induced by smoke inhalation through the nose-mouth plus lipopolysaccharide (LPS) or smoke exposure through the whole body plus LPS in rats, providing a new model for COPD. Methods Ninety male SD rats were randomly divided into normal control, whole body exposure, and smoke inhalation groups with 30 rats per group. The whole body exposure group was placed in a smoke box, whereby smoke contacted the whole body of the rats, whereas the smoke inhalation group inhaled smoke via the nose-mouth in a quantitative smoking device. Animals in both groups were exposed to smoke once a day for 60 min over 8 weeks. LPS (1 mg/ kg) was injected through the trachea on days 1, 7, 15, and 21 to induce the COPD model. Quality control of the smoke generated by the quantitative smoking device and smoking box included verification of the concentration stability and uniformity of the smoke particles and the particle size distribution of the smoke. At 4, 6, and 8 weeks of modeling, pulmonary function examination, the content of proinflammatory factors interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in alveolar lavage fluid, and histopathological examination were performed to compare the two modeling methods . Results Quantitative smoking devices produced smoke with a stable concentration of 1.1 mg/ L (total particles) and 0.1 mg/ L (nicotine), with a median mass particle size of 0.86 μm (nicotine) and a GSD of 2. 12. The deviation in stability and uniformity of the smoke concentration produced by the smoking box was obviously greater than that of the quantitative smoking device. Compared with the whole body exposure group, pulmonary function indexes FEV_0.2 / FVC and pulmonary compliance (Cdyn) in the smoke inhalation group were decreased significantly, and airway resistance (Penh) was increased significantly. IL-6 and TNF-α levels in alveolar lavage fluid of the smoke inhalation group were significantly increased at 6 weeks after modeling, and those in the whole body exposure group were increased at 8 weeks after modeling. The lesion severity of bronchial inflammation after modeling was similar in smoke inhalation and whole body exposure groups, but the degree of emphysema lesions in the nose-mouth inhalation group was more severe, and statistically significant differences in emphysema lesions appeared earlier in the nose-mouth inhalation group ( after 6 weeks of modeling) than in the whole body exposure group (after 8 weeks of modeling). The mean linear intercept (MLI) in the smoke inhalation group was increased significantly at 4 ~ 8 weeks of modeling, and the mean alveolar number (MAN) was decreased significantly at 6 ~ 8 weeks of modeling. MLI was increased significantly and MAN was decreased significantly in the whole body exposure group after 8 weeks of modeling. In the smoke inhalation group, significant abnormal changes were observed in pulmonary function indexes (FEV_0.2 / FVC, Cdyn, and Penh), cytokine levels in bronchoalveolar lavage fluid (IL-6 and TNF-α), and alveolar histopathological changes (bronchial severity and emphysema pathological score, MLI, and MAN) after modeling. However, the coefficient of variation (CV%) of each index was significantly lower than that in the whole body exposure group. Conclusion A 1. 0 mg/ kg LPS endotracheal drip combined with whole body smoke exposure or nose-mouth smoke inhalation both establish a typical rat COPD model. Inhaled smoke via the nose-mouth route shortened the modeling period. The model was established after 6 weeks of continuous smoke exposure, presenting typical symptoms of COPD (pulmonary ventilation dysfunction and broncho-lung chronic inflammatory infiltration accompanied by emphysema), and the difference between individual model animals was small (nose-mouth smoke inhalation vs smoke exposure, CV% values were smaller).