Comparison of PDE 4 inhibitors, rolipram and SB 207499 (ariflo), in a rat model of pulmonary neutrophilia

Pulm Pharmacol Ther. 2001;14(2):157-64. doi: 10.1006/pupt.2001.0291.

Abstract

Using a rat model of lipopolysaccharide (LPS)-induced pulmonary inflammation, the antiinflammatory activity of SB 207499 was evaluated and compared to that of the prototypic type-4 phosphodiesterase (PDE4) inhibitor, rolipram. In dose-response experiments, we found that rats exposed to 10 microg or 100 microg of intratracheal (it) LPS developed a prominent pulmonary inflammation, due to a significant increase in the number of recoverable bronchoalveolar lavage neutrophils. The pulmonary neutrophilia, provoked by the challenge of 10 microg LPS/rat, was significant at 2 h, peaked by 16 h, declined thereafter but remained elevated for up to 48 h. Additionally, the exposure of rats to 10 microg LPS caused the local pulmonary production of TNF- alpha. In contrast to the cellular influx, TNF- alpha production peaked at 2 h and rapidly declined to negligible levels by 8 h. While low levels were detected, the levels of IL-1 beta in bronchoalveolar lavage did not significantly differ from saline challenged animals. Rats pretreated with rolipram or SB 207499, displayed dose-dependent inhibition of the LPS-induced pulmonary inflammation. Nevertheless, the pulmonary production of TNF- alpha and IL-1 beta was unaffected by either SB 207499 or rolipram. When provoked with the 10 microg dose of LPS, adrenalectomized rats produced a similar 24 h induction of pulmonary neutrophilia. Pretreatment of adrenalectomized rats with the PDE4 inhibitors showed similar inhibitory results to those obtained in normal rats. In summary, we have shown, using a rat model of LPS-induced pulmonary neutrophilic inflammation, that the inhibitory activities of rolipram or SB207499 are not linked to the production of TNF- alpha or the inhibition of IL-1 beta, and occur independently of endogenous catecholamine or corticosteroid release.

Publication types

  • Comparative Study

MeSH terms

  • Adrenalectomy
  • Animals
  • Cyclohexanecarboxylic Acids / pharmacology*
  • Disease Models, Animal
  • Humans
  • Inflammation / pathology
  • Inflammation / veterinary
  • Interleukin-1 / biosynthesis
  • Lung Diseases / drug therapy*
  • Lung Diseases, Obstructive / immunology
  • Lung Diseases, Obstructive / physiopathology
  • Male
  • Neutrophils / drug effects*
  • Neutrophils / pathology
  • Nitriles
  • Phosphodiesterase Inhibitors / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Respiratory Distress Syndrome, Adult / immunology
  • Respiratory Distress Syndrome, Adult / physiopathology
  • Rolipram / pharmacology*
  • Tumor Necrosis Factor-alpha / biosynthesis

Substances

  • Cyclohexanecarboxylic Acids
  • Interleukin-1
  • Nitriles
  • Phosphodiesterase Inhibitors
  • Tumor Necrosis Factor-alpha
  • Cilomilast
  • Rolipram