A new mouse model of chronic obstructive pulmonary disease based on intratracheal instillation of cigarette smoke extract

The traditional cigarette smoke-induced chronic obstructive pulmonary disease (COPD) mouse model has a long period and its stability is not easily guaranteed. Based on the intratracheal instillation of cigarette smoke extract (CSE), this study aims to establish a CSE-induced COPD mouse model. C57BL/6J mice were used as model animals, except for the normal control group, animals in each group received intratracheal instillation of CSE. The airway reactivity and pulmonary function of the mice were measured using a small animal respiratory pulmonary function testing system, the leukocyte classification count in the bronchoalveolar lavage fluid (BALF) of the mice was determined using a blood and body fluid analyzer, the levels of inflammatory factors and neutrophil extracellular traps (NETs) in BALF were measured using enzyme-linked immunosorbent assay (ELISA), and the histopathological changes in the mouse lung tissue were detected using H&E staining method. The experiments were approved by the animal care and welfare committee of Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College (approval No. 00006301). The results of the study showed that after intratracheal instillation of CSE, the model group mice exhibited significant COPD-like pathological and functional changes, characterized by tachypnea, slow weight gain. H&E staining showed pathologic changes such as massive inflammatory infiltration of lung tissue, alveolar wall collapse and alveolar lumen dilatation. The leukocyte classification count (total leukocytes, neutrophils, eosinophils), the levels of inflammatory factors such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and NETs levels in the BALF were significantly increased compared to the normal control group (P < 0.01, P < 0.001). The index of airway reactivity, specific resistance, airway (sRaw) was significantly increased (P < 0.05), pulmonary function indicators such as peak expiratory flow (PEF), forced expiratory flow at 75% of forced vital capacity (FEF₇₅), dynamic lung compliance (Cdyn), forced expiratory volume in the first 100 ms (FEV₁₀₀), and the ratio of forced expiratory volume in the first 100 ms to forced vital capacity (FEV₁₀₀/FVC) were significantly reduced (P < 0.01), while the respiratory index (RI) was significantly increased (P < 0.05). Compared to the model group, roflumilast can significantly improve the inflammatory pathological changes and pulmonary function damage in model animals. In summary, the intratracheal instillation of CSE can rapidly establish a COPD mouse model, replicating the airway inflammation and decreased pulmonary function of COPD to a certain extent, and provides a new candidate animal model for the study of the pathological mechanism and drug screening evaluation of COPD.