Nonspecific phosphodiesterase inhibition attenuates liver injury in acute endotoxemia.

BACKGROUND

Endotoxemia is accompanied by pro-inflammatory cytokine production, generation of reactive oxygen species, and end-organ injury. Pentoxifylline (PTX), a methylxanthine derivative and phosphodiesterase inhibitor, is known for its anti-inflammatory properties, including down-regulation of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha synthesis. Its effects on liver function and hepatic histology following acute endotoxemia have not been investigated fully. We hypothesized that PTX would preserve liver architecture and function after intravenous lipopolysaccharide (LPS) injection.

METHODS

Anesthetized Sprague-Dawley rats received an i.v. bolus injection of LPS (5 mg/kg), LPS + PTX (25 mg/kg), or saline (sham). Plasma concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), TNF-alpha, IL-6, and nitrite were measured at different time points after LPS injection. Liver injury was graded according to a scoring system in a blinded fashion from 0 (normal) to 4 (severe) for hepatocellular necrosis, hemorrhage, and parenchymal and sinusoidal inflammatory infiltrates. Neutrophil infiltration was measured by counting myeloperoxidase (MPO)-positive stained cells. Nuclear factor (NF)-kappaB p-65 was measured by counting positive stained nuclei of hepatocytes and Kupffer cells (KC). Inducible nitric oxide synthase (iNOS) was evaluated by positively stained KC. Data are presented as mean +/- SEM. Analysis of variance with p < 0.05 was considered statistically significant.

RESULTS

Animals treated with PTX showed a significant reduction in liver injury score and neutrophil infiltration. Treatment with PTX significantly decreased TNF-alpha, IL-6, and the concentrations of AST and ALT when compared to LPS alone. In addition, a significant decrease in NF-kappaB-positive staining in hepatocytes and KC, as well as in KC iNOS immunostaining was observed in PTX-treated animals compared to the LPS group.

CONCLUSIONS

Pentoxifylline downregulates the inflammatory response significantly and decreases liver injury in acute endotoxemia.