title: Phosphodiesterase type 4 inhibition of activated polymorphonuclear leukocytes in a simulated extracorporeal circulation model.
abstract: OBJECTIVE
  Cardiopulmonary bypass is associated with a systemic inflammatory response syndrome and the risk of multiorgan injuries mediated by activated polymorphonuclear leukocytes. Phosphodiesterase type 4 is the predominant phosphodiesterase isozyme in polymorphonuclear leukocytes and plays a key role in the regulation of polymorphonuclear leukocyte activation. The aim of this study was to examine the effect of rolipram, a selective phosphodiesterase type 4 inhibitor, on the functional changes of polymorphonuclear leukocytes by using simulated extracorporeal circulation.
  
  
  METHODS
  Simulated extracorporeal circulation was established by recirculating heparinized human blood for 120 minutes on a membrane oxygenator with and without 10 micro mol/L rolipram. F-actin content and L-selectin and CD11b expression of polymorphonuclear leukocytes were measured by means of flow cytometry. Polymorphonuclear leukocyte deformability was evaluated with a microchannel array flow analyzer that had a similar diameter as the capillaries. Polymorphonuclear leukocyte elastase was measured with an enzyme immunoassay.
  
  
  RESULTS
  Rolipram reduced the increase of F-actin content of polymorphonuclear leukocytes and the increase of transit time of 100 micro L of blood sample through a microchannel. Rolipram reduced the increase of CD11b expression and the decrease of L-selectin expression of polymorphonuclear leukocytes. Rolipram reduced the release of elastase from polymorphonuclear leukocytes.
  
  
  CONCLUSIONS
  Rolipram inhibited the deformability change mediated by F-actin assembly, the changes in adhesion molecules, and the release of elastase from activated polymorphonuclear leukocytes in simulated extracorporeal circulation. This study suggests that phosphodiesterase type 4 inhibition could be a feasible therapeutic strategy to prevent the exaggerated inflammatory response related to cardiopulmonary bypass.
authors.affiliation: University of Tsukuba, Institute of Clinical Medicine, Tsukuba, Japan. tcvysato@md.jichi.ac.jp
authors.forename: Yukio
authors.initials: Y
authors.lastname: Sato
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hiramatsu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Homma
authors.forename: Shyoko
authors.initials: S
authors.lastname: Sato
authors.forename: Masataka
authors.initials: M
authors.lastname: Onizuka
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Sakakibara
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000199:Actins / Q000378:metabolism; D000328:Adult; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005112:Extracorporeal Circulation; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D018375:Neutrophil Activation; D009504:Neutrophils / Q000201:enzymology*; D010196:Pancreatic Elastase / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D020889:Rolipram / Q000494:pharmacology*
chemical_list: D000199:Actins; D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D010196:Pancreatic Elastase; D020889:Rolipram