title: The phosphodiesterase type IV inhibitor cilomilast decreases pro-inflammatory cytokine production from primary bronchial epithelial cells in lung transplantation patients.
abstract: BACKGROUND
  Bronchiolitis obliterans syndrome (BOS) remains the major cause of long-term morbidity and mortality after lung transplantation, and new therapeutic measures are needed. We speculated that cilomilast might reduce mediators of airway inflammation and angiogenesis from the airway epithelium, supporting a potential value in the treatment of BOS. We used an ex vivo primary bronchial epithelial cell culture (PBEC) model to investigate this hypothesis. Increasing evidence suggests the epithelium is central in stimulating both inflammatory and proliferative responses in the airway.
  
  
  METHODS
  Bronchial brushings were taken from 7 stable lung allograft recipients and were used to establish sub-confluent PBECs. The effect of incubation for 48 hours with 0.1 to 10 micromol/liter cilomilast on basal production of interleukin (IL)-8, IL-6, granulocyte macrophage colony-stimulating factor (GMCSF), and vascular endothelial growth factor (VEGF) were assayed by multiplex analyser.
  
  
  RESULTS
  There was a dose dependent fall in basal IL-8 and GMCSF levels with cilomilast. Median change for IL-8 was -25% (range, -66% to 5%; p = 0.035) at 1 micromol/liter , and -40% (range, -72% to -20; p = 0.022) at 10 micromol/liter. Median GMSCF change was -34% (range, -70% to 16%; p = 0.05) at 1 micromol/liter, and 37% (range, -80% to -8%; p = 0.04) at 10 micromol/liter. There were no effects on VEGF.
  
  
  CONCLUSIONS
  The phosphodiesterase type IV inhibitor cilomilast reduced IL-8 and GMCSF release from PBECs. These cytokines are associated with the persistence of airway neutrophilic inflammation and airway remodelling seen in obliterative bronchiolitis. These ex vivo results suggest a potential for cilomilast in the treatment of BOS, which would need to be evaluated in appropriate clinical studies.
authors.affiliation: The Applied Immunobiology and Transplantation Research Group Institute of Cellular Medicine, Newcastle-upon-Tyne, United Kingdom.
authors.forename: Des M
authors.initials: DM
authors.lastname: Murphy
authors.forename: Chris
authors.initials: C
authors.lastname: Ward
authors.forename: Ian A
authors.initials: IA
authors.lastname: Forrest
authors.forename: Gail
authors.initials: G
authors.lastname: Pritchard
authors.forename: Debbie
authors.initials: D
authors.lastname: Jones
authors.forename: Rachel
authors.initials: R
authors.lastname: Stovold
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Fisher
authors.forename: Tim E
authors.initials: TE
authors.lastname: Cawston
authors.forename: Jim L
authors.initials: JL
authors.lastname: Lordan
authors.forename: Paul A
authors.initials: PA
authors.lastname: Corris
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D001980:Bronchi / Q000378:metabolism*; D002264:Carboxylic Acids / Q000008:administration & dosage / Q000627:therapeutic use; D002478:Cells, Cultured; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D016209:Interleukin-8 / Q000037:antagonists & inhibitors; D016040:Lung Transplantation; D009570:Nitriles / Q000008:administration & dosage / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D015105:3',5'-Cyclic-AMP Phosphodiesterases; D002264:Carboxylic Acids; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D018836:Inflammation Mediators; D016209:Interleukin-8; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D000093242:Interleukin-6 Inhibitors; C467484:VEGFA protein, human; C433247:Cilomilast