title: Inhibition of phosphodiesterase 9A reduces cytokine-stimulated in vitro adhesion of neutrophils from sickle cell anemia individuals.
abstract: OBJECTIVE
  Leukocyte adhesion to vessel walls may initiate vaso-occlusion in sickle cell anemia (SCA); however, the extent to which inflammation participates in this mechanism is not understood. This in vitro study investigated whether inflammatory molecules, commonly augmented in SCA, can affect neutrophil adhesive properties and whether cyclic guanosine monophosphate (cGMP)-elevating agents can inhibit such adhesion.
  
  
  METHODS
  Effects of Interleukin 8 (IL-8), tumor necrosis factor-α (TNF-α), granulocyte macrophage-colony stimulating factor (GM-CSF) cytokines, BAY 73-6691 [phosphodiesterase (PDE)-9A-inhibitor], and BAY 41-2271 (guanylate-cylase stimulator) on the adhesive properties of neutrophils from healthy control (CON) and steady-state SCA individuals were determined using static-adhesion assays.
  
  
  RESULTS
  SCA neutrophils demonstrated increased adhesive properties, compared to CON neutrophils; IL-8, TNF-α and GM-CSF increased CON neutrophil adhesion and further increased SCA neutrophil adhesion to fibronectin (FN). The PDE9A inhibitor, BAY-73-6691, significantly reduced basal CON neutrophil and SCA neutrophil adhesion; this was accompanied by decreased SCA neutrophil surface expressions of the L-selectin and CD11b adhesion molecules. BAY-73-6691 also significantly reduced cytokine-stimulated CON neutrophil and SCA neutrophil adhesion to FN; however, this was not accompanied by alterations in adhesion-molecule presentation.
  
  
  CONCLUSIONS
  The chronic inflammatory nature of SCA may contribute to leukocyte adhesive functions in SCA. Furthermore, elevation of leukocyte cGMP may be an interesting approach for inhibition of leukocyte adhesion to the vessel wall, even in the presence of inflammatory stimuli.
authors.affiliation: Hematology and Hemotherapy Center-Instituto Nacional de Ciência e Tecnologia do Sangue, University of Campinas-UNICAMP, Campinas, SP 13083-970, Brazil.
authors.forename: Lediana Iagalo
authors.initials: LI
authors.lastname: Miguel
authors.forename: Camila B
authors.initials: CB
authors.lastname: Almeida
authors.forename: Fabiola
authors.initials: F
authors.lastname: Traina
authors.forename: Andreia A
authors.initials: AA
authors.lastname: Canalli
authors.forename: Venina M
authors.initials: VM
authors.lastname: Dominical
authors.forename: Sara T O
authors.initials: ST
authors.lastname: Saad
authors.forename: Fernando F
authors.initials: FF
authors.lastname: Costa
authors.forename: Nicola
authors.initials: N
authors.lastname: Conran
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000293:Adolescent; D000328:Adult; D000755:Anemia, Sickle Cell / Q000503:physiopathology*; D002448:Cell Adhesion / Q000187:drug effects*; D006152:Cyclic GMP / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D055815:Young Adult
chemical_list: D016207:Cytokines; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C116137:PDE9A protein, human; D006152:Cyclic GMP