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

1 The effects of phosphodiesterase (PDE)4 and TNF-alpha inhibition were ass essed on the local and remote injuries following intestinal ischaemia and r eperfusion (I/R) injury in rats. 2 The PDE4 inhibitor rolipram dose-dependently (1 - 10 mg kg(-1)) suppresse d the local (intestine) and remote (lung) increases in vascular permeabilit y and neutrophil recruitment following mild I/R injury. SB207499 (ariflo), a structurally-distinct PDE4 inhibitor, also suppressed the injuries follow ing mild I/R injury. 3 In a severe model of I/R injury, treatment with rolipram (10 mg kg(-1)) p artially reversed the local and remote increases in vascular permeability, neutrophil recruitment, intestinal haemorrhage and intestinal LTB4 concentr ations. The anti-TNF-alpha anti-serum was more effective than rolipram at i nhibiting 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 inhibit ed the elevation of this cytokine in serum. Rolipram had little effect on t he increases of IL-1 beta concentrations in lung and serum, whereas treatme nt with anti-TNF-alpha, markedly increased the concentration of this cytoki ne. Concentrations of IL-10 rose significantly in the lung and serum and th ese increases were blocked by rolipram or anti-TNF-alpha. 5 The capacity of PDE4 inhibitors to block the recruitment of neutrophils i nto tissues, the production of LTB4 and of the pro-inflammatory cytokines T NF-alpha, IL-1 beta and IL-6 appear to underlie their anti-inflammatory eff ects in our model of I/R injury. Overall, PDE4 inhibition was less effectiv e than inhibition of TNF-alpha for protection against I/R injury.