Efficacy of Pentoxifylline in Smoking Combined with Lipopolysaccharide Atomization Exposure Induced Emphysema in Mice

Objective To explore the effect of pentoxifylline dose and administration mode on lung pathology and inflammation induced by atomization exposure of cigarettes combined with lipopolysaccharides. Metholds: Female C57BL/6 mice were exposed to smoke (CS) + lipopolysaccharide (LPS) and pseudosmoke (SCS) for 10 weeks, and from week 9, animals were randomized into separate interventions with nebulized pentoxifylline (different doses), theophylline, budesonide suspension for 2 weeks, and a co-solvent control group was established. Animals are euthanized on the weekend of the 10th week. The ELISA method detected TNF-α, IL-8 and IL-1β expression in alveolar lavage fluid (BALF). After homogenization, the expression of MMP-12 and HDAC2 activity were detected by ELISA method; H&E staining of lung tissue sections to measure alveolar mean intercept (Lm) and alveolar destruction index (ADI); Reye-Jimsa staining assay for the determination of cell classification and quantity in BALF. Results The inflammatory reaction of lung after chronic CS + LPS exposure is enhanced, which is manifested as TNF-α,IL-8,IL-1 β and MMP-12 increase(CS + LPS vs SCS: TNF-α 68.70 ± 1.75pg/ml vs 32.67 ± 0.90pg/ml, p  < 0.05; IL-8 45.66 ± 1.72pg/ml vs 15.72 ± 1.84pg/ml, p  < 0.05; IL-1β 36.81 ± 1.02pg/ml vs 11.58 ± 0.76pg/ml, p  < 0.05; MMP-12 103.57 ± 1.87ng/ml vs 31.96 ± 1.84ng/ml, p  < 0.05). Furthermore, the HDAC2 activity decreased(CS + LPS vs SCS:8.86 ± 0.29U/ml vs 20.44 ± 0.60U/ml, p  < 0.05), Lm and ADI increased(CS + LPS vs SCS: Lm,45.58 ± 0.50um vs 24.14 ± 2.93um, p  < 0.05; ADI,51.90 ± 1.90% vs 6.29 ± 0.20%, p  < 0.05).Meanwhile, the total cell count in BALF augmented(CS + LPS vs SCS:156.20 ± 18.88 10^5/ml vs 28.20 ± 3.50 10^5/ml, p  < 0.05). Budesonide suspension has no significant effect on HDAC2 activity. Different doses of pentoxifylline (PTX) and theophylline (THEO) can restore part of HDAC2 activity ( p  < 0.05). Conclusions Aerosol inhalation of pentoxifylline and theophylline could reduce lung inflammation induced by cigarette smoke combined with lipopolysaccharide exposure, reduce the expression of TNF-α,IL-8,IL-1β and MMP-12,and restore the decrease in HDAC2 activity induced by long-term smoke and lipopolysaccharide exposure, while inhalation of budesonide suspension alone had no effect on the activity of lung HDAC2. The recovery of HDAC2 activity is related to the nebulized inhalation dose of pentoxifylline, but more experimental studies are needed to determine the optimal concentration.