Phosphodiesterase activity in neutrophils from horses with chronic obstructive pulmonary disease

Neutrophils are recruited to the lungs of horses with chronic obstructive p ulmonary disease (COPD) and exhibit increased activity after antigen challe nge. Phosphodiesterase type4 (pDE4) inhibitors have been shown to attenuate human neutrophil activation. The aim of this study was to establish the PD E isoenzyme profile of equine neutrophils using isoenzyme selective inhibit ors to determine if these compounds should be evaluated in horses with COPD . Total cAMP and cGMP dependent PDE activity was no different in neutrophil s from normal (156.2+/-7.1 and 6.8+/-0.6 pmol/min/mg for cAMP and cGMP, res pectively) and COPD susceptible horses (146.0+/-10.2 and 5.5+/-0.6 pmol/min /mg for cAMP and cGMP, respectively). The PDE4 inhibitors, CDP840 and rolip ram, caused significant, concentration related and almost complete inhibiti on of PDE activity (IC50 values = 8.8 +/- 0.1 x 10(-9) and 7.3 +/- 0.2 x 10 (-9) M for CDP840; 1.2 +/-. 0.1 x 10(-6) and 1.1 +/- 0.1 x 10(-6) M for rol ipram in normal and COPD susceptible horses, respectively). The inhibitory effects of the mixed PDES/PDE4 inhibitor, zardaverine were of similar magni tude and potency to rolipram. However, the limited inhibitory effects of th e PDE3 inhibitor, siguazodan, suggest that zardaverine is acting primarily via PDE4 inhibition. These results indicate that PDE4 is the predominant is oenzyme present in the equine neutrophil and inhibition of PDE activity usi ng selective PDE4 inhibitors may, therefore, modulate equine neutrophil act ivation in horses with COPD. (C) 2000 Elsevier Science B.V. All rights rese rved.