Effects of Pentoxifylline on Inflammatory Cytokine Expression and Acute Pleuropneumonia in Swine

https://doi.org/10.1078/0171-2985-00108Get rights and content

Summary

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 a (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)-1b mRNA levels also was achieved in macrophages. Pentoxifylline did not affect either IL- la 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.

References (47)

  • J. Nicolet

    Actinobacillus pleuropneumoniae

  • P.J. Fedorka-Cray et al.

    Actinobacillus (Haemophilus) pleuropneumoniae. Part I. history, epidemiology, serotyping, and treatment

    Compend Cont Educ

    (1993)
  • U.E. Idris et al.

    Pulmonary lesions in mice inoculated with Actinobacillus pleuropneumoniae hemolysin and lipopolysaccharide

    Vet. Pathol.

    (1993)
  • F.A. Udeze et al.

    Role of Haemophilus pleuropneumoniae lipopolysaccharide endotoxin in the pathogenesis of porcine Haemophilus pleuropneumonia

    Am. J. Vet. Res.

    (1987)
  • M.J. Baarsch et al.

    Inflammatory cytokine expression in swine experimentally infected with Actinobacillus pleuropneumoniae

    Infect. Immun.

    (1995)
  • M.J. Baarsch et al.

    Pathophysiological correlates of acute porcine pleuropneumonia

    Amer. J. Vet. Res.

    (2000)
  • D.F. Morrison et al.

    Interleukin–10 gene therapy-mediated amelioration of bacterial pneumonia

    Infect. Immun.

    (2000)
  • R.L. Gibson et al.

    Group B Streptococcus induces tumor necrosis factor in neonatal pigs. Effect of the tumor necrosis factor inhibitor pentoxifylline on hemodynamics and gas exchange

    Am. Rev. Respir. Dis.

    (1991)
  • H. Hoffmann et al.

    Early post-treatment with pentoxifylline or dibutyryl cAMP attenuates Escherichia coli-induced acute lung injury in guinea pigs

    Am. Rev. Respir. Dis.

    (1991)
  • D.M. Aviado et al.

    Pharmacology of pentoxifylline, a hemorrheologic agent for the treatment of intermittent claudication

    Angiology

    (1984)
  • G.L. Mandell

    ARDS, neutrophils, and pentoxifylline

    Am. Rev. Respir. Dis.

    (1988)
  • A. Ishizaka et al.

    Attenuation of acute lung injury in septic guinea pigs with pentoxifylline

    Am. Rev. Respir. Dis.

    (1988)
  • U.F. Schade et al.

    Increase of survival rate by pentoxifylline in endotoxic shock

  • Cited by (15)

    • Infection dynamics and acute phase response of an Actinobacillus pleuropneumoniae field isolate of moderate virulence in pigs

      2014, Veterinary Microbiology
      Citation Excerpt :

      Previous studies of other swine respiratory diseases have reported a marked expression of pro-inflammatory cytokines only at the lung level without significant changes in their serum concentrations, making it necessary to examine samples from the lung parenchyma to determine the events occurring in the respiratory tracts of infected pigs (Gómez-Laguna et al., 2013). Thus, according to previous in vitro (Myers et al., 2002; Benga et al., 2009; Chen et al., 2011) and in vivo (Baarsch et al., 2000; Benga et al., 2009) studies, IL-1β and/or to a lesser extent TNF-α might be expressed at the lung level displaying a paracrine effect in the onset of lung lesions in PCP. Our results affirm the role of IL-6 in the induction of an acute phase response after Ap6 infection.

    • Advances in swine immunology help move vaccine technology forward

      2014, Veterinary Immunology and Immunopathology
      Citation Excerpt :

      The general molecular features of innate anti-viral and anti-bacterial responses that have been elucidated primarily in murine host–pathogen models provide useful models for investigation of host defense in veterinary species. In swine, for example, respiratory infection by the gram-negative bacteria, Actinobacillus pleuropneumoniae, induces an acute, robust lung cytokine response characterized by IL-1, IL-6 and IL-8 production (Baarsch et al., 1995, 2000; Morrison et al., 2000; Myers et al., 2002; Van Reeth et al., 2002). However, despite the presence of bacterial LPS and CpG DNA, there is no induction in vivo of tumor necrosis factor (TNF), the classical inflammatory cytokine molecule and effector product of NF-κB activation, even though in vitro incubation of alveolar macrophages with boiled extracts of A. pleuropneumoniae readily induces TNF (Baarsch et al., 1995, 2000).

    • The combination of PRRS virus and bacterial endotoxin as a model for multifactorial respiratory disease in pigs

      2004, Veterinary Immunology and Immunopathology
      Citation Excerpt :

      Pentoxifylline can inhibit neutrophil adhesion and activation, improve blood perfusion and cause bronchodilatation (Tighe et al., 1990; Cortijo et al., 1993). Myers et al. (2002) studied the effect of pentoxifylline on acute pleuropneumonia caused by A. pleuropneumoniae in swine. They found that a dose of 20 mg/kg s.c. had no effect on the expression of proinflammatory cytokines in the lungs.

    View all citing articles on Scopus
    View full text