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.
Coimbra
Raul
R
Division of Trauma and Surgical Critical Care, Department of Surgery, University of California San Diego School of Medicine, San Diego, California 92103-8896, USA. rcoimbra@ucsd.edu
Porcides
Rafael Dib
RD
Melbostad
Heidi
H
Loomis
William
W
Tobar
Maria
M
Hoyt
David B
DB
Wolf
Paul
P
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D019446:Endotoxemia / Q000188:drug therapy*; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000097:blood; D008107:Liver Diseases / Q000517:prevention & control*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D010431:Pentoxifylline / Q000627:therapeutic use*; D009195:Peroxidase / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D015850:Interleukin-6; D016328:NF-kappa B; D009573:Nitrites; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D010431:Pentoxifylline