title: Differential inhibition of equine neutrophil function by phosphodiesterase inhibitors.
abstract: Neutrophils are recruited to the lungs of horses with chronic obstructive pulmonary disease (COPD) and exhibit increased activity after antigen challenge, which may contribute to inflammation and lung damage. Inhibition of phosphodiesterase isoenzymes (PDEs) has been shown to attenuate human neutrophil functions including superoxide production, leukotriene (LT)B4 biosynthesis, enzyme and chemokine release. As equine neutrophils contain predominantly the isoenzyme, PDE4, the present study was undertaken to investigate the effects of rolipram, a PDE4 inhibitor, on equine neutrophil function. For comparison, the effects of the nonselective PDE inhibitor, theophylline, were examined. Cells from both normal horses and COPD horses in remission were 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, respectively, in response to 10(-7) M human recombinant (hr) C5a] and theophylline (19.0 +/- 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 serum 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 results demonstrate that the effects of PDE inhibitors on equine neutrophils are both stimulus and function dependent. The PDE4 inhibitors may reduce neutrophil activation in vivo in horses with COPD.
authors.affiliation: Department of Veterinary Basic Sciences, The Royal Veterinary College, Hawkshead Campus, North Mymms, Hertfordshire AL9 7TA, UK. krickard@rvc.ac.uk
authors.forename: K J
authors.initials: KJ
authors.lastname: Rickards
authors.forename: C P
authors.initials: CP
authors.lastname: Page
authors.forename: P
authors.initials: P
authors.lastname: Lees
authors.forename: F M
authors.initials: FM
authors.lastname: Cunningham
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D006734:Horse Diseases / Q000188:drug therapy*; D006736:Horses / Q000378:metabolism*; D008173:Lung Diseases, Obstructive / Q000188:drug therapy / Q000662:veterinary*; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020889:Rolipram / Q000494:pharmacology* / Q000627:therapeutic use; D013481:Superoxides / Q000378:metabolism; D013806:Theophylline / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D010726:Phosphodiesterase Inhibitors; D013481:Superoxides; D013806:Theophylline; D020889:Rolipram