Effects of pentoxifylline on inflammatory cytokine expression and acute pleuropneumonia in swine.
Pentoxifylline, a methylxanthine derivative and nonspecific type 4 phosphodiesterase inhibitor, has been used to improve survival of animals with sepsis and to attenuate lung injury in acute lung inflammation. The purpose of this study was to examine whether pentoxifylline would inhibit the expression of inflammatory cytokines, particularly tumor necrosis factor alpha (TNF), and thereby decrease the pathophysiology of acute porcine pleuropneumonia. E. coli lipopolysaccharide (LPS) and bacterial extracts of A. pleuropneumoniae--induced elevations in TNF mRNA which were fully abrogated by addition of pentoxifylline in both alveolar macrophage and neutrophil cultures. A 30% reduction in the level of LPS-induced interleukin (IL)-1beta mRNA levels also was achieved in macrophages. Pentoxifylline did not affect either IL-1alpha or IL-8 expression in vitro. Pentoxifylline therapy in vivo significantly reduced the number of band neutrophils in swine but did not reduce the pathology associated with pleuropneumonia, including changes in serum zinc, iron, or haptoglobin. Neither did it alter TNF, IL-1, IL-6, or IL-8 expression. Measurement of pentoxifylline and its metabolites in pig sera suggested that efficacious doses of pentoxifylline were probably not achieved in vivo. However, subcutaneous doses of pentoxifylline higher than 25 mg/kg produced transient diarrhea, vomiting, and tremors. These results suggest that pentoxifylline is an effective pharmacological tool for the dissection of cytokine regulation in vitro, but inhibitory concentrations may not be achievable for in vivo pharmacological use in swine.
Myers
Michael J
MJ
Division of Animal Research, Center for Veterinary Medicine, US FDA, Laurel, MD, USA. mmyers@cvm.fda.gov
Baarsch
Mary J
MJ
Murtaugh
Michael P
MP
D000189:Actinobacillus Infections / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000662:veterinary*; D016977:Actinobacillus pleuropneumoniae / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002478:Cells, Cultured; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis*; D016209:Interleukin-8 / Q000096:biosynthesis*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D010431:Pentoxifylline / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D013552:Swine; D013553:Swine Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D014202:Tremor / Q000139:chemically induced; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects; D014839:Vomiting / Q000139:chemically induced
D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D010431:Pentoxifylline