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已发表论文
雾化己酮可可碱在香烟烟雾和雾化脂多糖诱导肺气肿小鼠模型中的疗效
Authors Hu Z, Yu Y, Peng T, Niu R, Li Z, Wang W, Zheng X, Zhang J
Received 19 July 2025
Accepted for publication 28 December 2025
Published 13 January 2026 Volume 2026:21 554927
DOI https://doi.org/10.2147/COPD.S554927
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Prof. Dr. Richard Russell
Zhenghao Hu,1 Yaling Yu,1 Tianfeng Peng,2 Ruijie Niu,1 Zhuanyun Li,3 Wenjing Wang,4,5 Xiaofang Zheng,1 Jinnong Zhang1
1Department of Emergency Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 4Department of Critical Care Medicine, Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of China; 5Henan Key Laboratory for Critical Care Medicine, Zhengzhou, People’s Republic of China
Correspondence: Jinnong Zhang, Email zjnwhhb@163.com
Objective: To investigate the impact of pentoxifylline dosage on lung pathological changes and inflammation triggered by the combined exposure to cigarette smoke and aerosolized lipopolysaccharides.
Methods: Female C57BL/6 mice were subjected to either cigarette smoke (CS) plus lipopolysaccharide (LPS) exposure or sham smoke (SCS) exposure for a duration of 10 weeks. Starting from the 9th week, the mice were randomly assigned to distinct intervention groups, where they received nebulized treatments of pentoxifylline (at varying doses), theophylline, or budesonide suspension for 2 weeks. A co-solvent control group was also included. At the end of the 10th week, the mice were euthanized. Enzyme-linked immunosorbent assay (ELISA) was employed to detect the expression levels of tumor necrosis factor-α (TNF-α), keratinocyte chemoattractant/C-X-C motif chemokine ligand 1 (KC/CXCL1, the murine functional homolog), and interleukin-1β (IL-1β) in bronchoalveolar lavage fluid (BALF). After tissue homogenization, ELISA was also used to measure the expression of matrix metalloproteinase-12 (MMP-12) and the level of histone deacetylase 2 (HDAC2). Hematoxylin and eosin (H&E) staining was performed on lung tissue sections to determine the alveolar mean linear intercept (Lm) and alveolar destruction index (ADI). Additionally, Wright-Giemsa staining was utilized for the classification and quantification of cells in BALF.
Results: Chronic exposure to CS+LPS resulted in a significant exacerbation of pulmonary inflammation, which was characterized by elevated levels of TNF-α, KC/CXCL1, IL-1β, and MMP-12 (CS+LPS group vs SCS group, all p< 0.05). Moreover, a notable reduction in HDAC2 level was observed, accompanied by significant increases in Lm and ADI (all p< 0.05). The total cell count in BALF was also significantly higher in the CS+LPS group (p< 0.05). Budesonide treatment led to a significant reduction in the levels of inflammatory cytokines and MMP-12; however, it had no significant effect on HDAC2 level. Both pentoxifylline (PTX) at different doses and theophylline (THEO) effectively decreased the expression of inflammatory markers and increased HDAC2 level (p< 0.05). Notably, none of the treatments resulted in a significant improvement in Lm, whereas ADI was significantly reduced following treatment. Although THEO induced a reduction in TNF-α levels, this change did not reach statistical significance.
Conclusion: Nebulized pentoxifylline and theophylline can alleviate lung inflammation induced by CS and LPS exposure, as evidenced by the decreased expression of TNF-α, KC/CXCL1, IL-1β, and MMP-12, and the restoration of HDAC2 level (which was reduced by CS+LPS exposure). In contrast, budesonide alone was capable of reducing inflammation but failed to exert an impact on HDAC2 level. A numerical trend indicated that pentoxifylline at a concentration of 22.0 mg/mL might exhibit greater efficacy; however, no statistically significant differences were observed among the various PTX doses tested. Further research is required to identify the optimal concentration of pentoxifylline for this application.
Keywords: pulmonary inflammation, cigarette smoke, pentoxifylline, histone deacetyltransferase 2, cytokines
1Department of Emergency Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 4Department of Critical Care Medicine, Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of China; 5Henan Key Laboratory for Critical Care Medicine, Zhengzhou, People’s Republic of China
Correspondence: Jinnong Zhang, Email zjnwhhb@163.com
Objective: To investigate the impact of pentoxifylline dosage on lung pathological changes and inflammation triggered by the combined exposure to cigarette smoke and aerosolized lipopolysaccharides.
Methods: Female C57BL/6 mice were subjected to either cigarette smoke (CS) plus lipopolysaccharide (LPS) exposure or sham smoke (SCS) exposure for a duration of 10 weeks. Starting from the 9th week, the mice were randomly assigned to distinct intervention groups, where they received nebulized treatments of pentoxifylline (at varying doses), theophylline, or budesonide suspension for 2 weeks. A co-solvent control group was also included. At the end of the 10th week, the mice were euthanized. Enzyme-linked immunosorbent assay (ELISA) was employed to detect the expression levels of tumor necrosis factor-α (TNF-α), keratinocyte chemoattractant/C-X-C motif chemokine ligand 1 (KC/CXCL1, the murine functional homolog), and interleukin-1β (IL-1β) in bronchoalveolar lavage fluid (BALF). After tissue homogenization, ELISA was also used to measure the expression of matrix metalloproteinase-12 (MMP-12) and the level of histone deacetylase 2 (HDAC2). Hematoxylin and eosin (H&E) staining was performed on lung tissue sections to determine the alveolar mean linear intercept (Lm) and alveolar destruction index (ADI). Additionally, Wright-Giemsa staining was utilized for the classification and quantification of cells in BALF.
Results: Chronic exposure to CS+LPS resulted in a significant exacerbation of pulmonary inflammation, which was characterized by elevated levels of TNF-α, KC/CXCL1, IL-1β, and MMP-12 (CS+LPS group vs SCS group, all p< 0.05). Moreover, a notable reduction in HDAC2 level was observed, accompanied by significant increases in Lm and ADI (all p< 0.05). The total cell count in BALF was also significantly higher in the CS+LPS group (p< 0.05). Budesonide treatment led to a significant reduction in the levels of inflammatory cytokines and MMP-12; however, it had no significant effect on HDAC2 level. Both pentoxifylline (PTX) at different doses and theophylline (THEO) effectively decreased the expression of inflammatory markers and increased HDAC2 level (p< 0.05). Notably, none of the treatments resulted in a significant improvement in Lm, whereas ADI was significantly reduced following treatment. Although THEO induced a reduction in TNF-α levels, this change did not reach statistical significance.
Conclusion: Nebulized pentoxifylline and theophylline can alleviate lung inflammation induced by CS and LPS exposure, as evidenced by the decreased expression of TNF-α, KC/CXCL1, IL-1β, and MMP-12, and the restoration of HDAC2 level (which was reduced by CS+LPS exposure). In contrast, budesonide alone was capable of reducing inflammation but failed to exert an impact on HDAC2 level. A numerical trend indicated that pentoxifylline at a concentration of 22.0 mg/mL might exhibit greater efficacy; however, no statistically significant differences were observed among the various PTX doses tested. Further research is required to identify the optimal concentration of pentoxifylline for this application.
Keywords: pulmonary inflammation, cigarette smoke, pentoxifylline, histone deacetyltransferase 2, cytokines