Efficacy of Nebulized Pentoxifylline in a Mouse Model of Emphysema Induced by Cigarette Smoke and Aerosolized Lipopolysaccharide.

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.