Differential inhibition of equine neutrophil function by phosphodiesteraseinhibitors

Neutrophils are recruited to the lungs of horses with chronic obstructive p ulmonary disease (COPD) and exhibit increased activity after antigen challe nge, which may contribute to inflammation and lung damage. Inhibition of ph osphodiesterase isoenzymes (PDEs) has been shown to attenuate human neutrop hil functions including superoxide production, leukotriene (LT)B-4 biosynth esis, enzyme and chemokine release. As equine neutrophils contain predomina ntly the isoenzyme, PDE4, the present study was undertaken to investigate t he effects of rolipram, a PDE4 inhibitor, on equine neutrophil function. Fo r comparison, the effects of the nonselective PDE inhibitor theophylline, w ere examined. Cells from both normal horses and COPD horses in remission we re used. Superoxide production was significantly inhibited by both rolipram [32.2 +/- 2.6 vs. 10.1 +/- 1.1 nmol/10(6) cells and 49.8 +/- 6.8 vs. 22.7 +/- 2.2 nmol/10(6) cells for normal and COPD susceptible horses, respective ly, in response to 10(-7) M human recombinant (hr) C5a] and theophylline (1 9.0 +/- 0.6 vs. 10.2 +/- 0.6 nmol/10(6) cells and 24.3 +/- 2.1 vs. 10.7 +/- 0.9 nmol/10(6) cells for normal and COPD susceptible horses, respectively, in response to 10(-7) M C5a). However, superoxide production induced by se rum treated zymosan was inhibited only by theophylline (10(-3) M). Neither hrC5a- nor platelet activating factor (PAF)-induced neutrophil adherence to fibronectin coated plastic was reduced by rolipram (10(-5) M). These resul ts demonstrate that the effects of PDE inhibitors on equine neutrophils are both stimulus and function dependent. The PDE4 inhibitors may reduce neutr ophil activation in vivo in horses with COPD.