Effects of inhibition of PDE4 and TNF‐α on local and remote injuries following ischaemia and reperfusion injury

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Abstract
The effects of phosphodiesterase (PDE)4 and TNF‐α inhibition were assessed on the local and remote injuries following intestinal ischaemia and reperfusion (I/R) injury in rats. 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. 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 LTB4 concentrations. The anti‐TNF‐α anti‐serum was more effective than rolipram at inhibiting local and remote injuries and prevented the lethality associated with severe I/R. Rolipram and anti‐TNF‐α prevented the increase in the concentrations of TNF‐α 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‐1ß concentrations in lung and serum, whereas treatment with anti‐TNF‐α 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‐α. The capacity of PDE4 inhibitors to block the recruitment of neutrophils into tissues, the production of LTB4 and of the pro‐inflammatory cytokines TNF‐α, IL‐1ß 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‐α for protection against I/R injury. British Journal of Pharmacology (2001) 134, 985–994; doi:10.1038/sj.bjp.0704336