Effects of inhibition of PDE4 and TNF-alpha on local and remote injuries following ischaemia and reperfusion injury

Br J Pharmacol. 2001 Nov;134(5):985-94. doi: 10.1038/sj.bjp.0704336.


1. The effects of phosphodiesterase (PDE)4 and TNF-alpha inhibition were assessed on the local and remote injuries following intestinal ischaemia and reperfusion (I/R) injury in rats. 2. The PDE4 inhibitor rolipram dose-dependently (1 - 10 mg kg(-1)) suppressed the local (intestine) and remote (lung) increases in vascular permeability and neutrophil recruitment following mild I/R injury. SB207499 (ariflo), a structurally-distinct PDE4 inhibitor, also suppressed the injuries following mild I/R injury. 3. In a severe model of I/R injury, treatment with rolipram (10 mg kg(-1)) partially reversed the local and remote increases in vascular permeability, neutrophil recruitment, intestinal haemorrhage and intestinal LTB(4) concentrations. The anti-TNF-alpha anti-serum was more effective than rolipram at inhibiting local and remote injuries and prevented the lethality associated with severe I/R. 4. Rolipram and anti-TNF-alpha prevented the increase in the concentrations of TNF-alpha in the lung and intestine, but rolipram only partially inhibited the elevation of this cytokine in serum. Rolipram had little effect on the increases of IL-1 beta concentrations in lung and serum, whereas treatment with anti-TNF-alpha markedly increased the concentration of this cytokine. Concentrations of IL-10 rose significantly in the lung and serum and these increases were blocked by rolipram or anti-TNF-alpha. 5. The capacity of PDE4 inhibitors to block the recruitment of neutrophils into tissues, the production of LTB(4) and of the pro-inflammatory cytokines TNF-alpha, IL-1 beta and IL-6 appear to underlie their anti-inflammatory effects in our model of I/R injury. Overall, PDE4 inhibition was less effective than inhibition of TNF-alpha for protection against I/R injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • Animals
  • Capillary Permeability / drug effects
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Cyclohexanecarboxylic Acids / pharmacology
  • Cytokines / blood
  • Cytokines / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Immune Sera / pharmacology*
  • Male
  • Neutrophils / cytology
  • Neutrophils / drug effects
  • Nitriles
  • Phosphodiesterase Inhibitors / pharmacology*
  • Rats
  • Rats, Wistar
  • Reperfusion Injury / blood
  • Reperfusion Injury / mortality
  • Reperfusion Injury / prevention & control*
  • Rolipram / pharmacology
  • Survival Rate
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / immunology


  • Cyclohexanecarboxylic Acids
  • Cytokines
  • Immune Sera
  • Nitriles
  • Phosphodiesterase Inhibitors
  • Tumor Necrosis Factor-alpha
  • Cilomilast
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Rolipram