title: Evaluation of oral corticosteroids and phosphodiesterase-4 inhibitor on the acute inflammation induced by inhaled lipopolysaccharide in human.
abstract: BACKGROUND
  Endotoxins are pro-inflammatory substances present in the environment. In man, inhalation of its purified derivative lipopolysaccharide (LPS) induces inflammation related to macrophages and neutrophils. Corticosteroids and phosphodiesterase (PDE)-4 inhibitors have inhibiting effects on macrophages and neutrophils, respectively. This study investigated the effect of prednisolone and of the PDE-4 inhibitor cilomilast on the LPS-induced acute inflammation.
  
  
  METHODS
  The study was a placebo-controlled, double-blind crossover design. On three occasions, at 2 weeks interval, 16 healthy subjects inhaled 50 microg LPS after a 6-day treatment with cilomilast (15 mg bd), prednisolone (10 mg bd) or placebo. For the assessment of the inflammatory response, induced sputum was obtained before inclusion and 6h post-LPS while blood samples were collected before, 6 and 24 h post-LPS.
  
  
  RESULTS
  Inhaled LPS induced an increase in sputum neutrophils (p<0.0001), logMMP-9 (p<0.05), logMMP-9/TIMP-1 (p<0.01) and logTNF-alpha (p<0.02). At the blood level there were significant rise in neutrophilia (p<0.001), E-selectin (p<0.02), C-reactive protein (CRP) (p<0.001) and LPS-binding protein (p<0.001). There was both a slight, but not significant, increase in body temperature and decrease in forced expiratory volume in 1 s (FEV(1)). Neither prednisolone nor cilomilast had protective effect on the LPS-induced airways' inflammation. The LPS-induced CRP acute-phase protein of inflammation (0.58+/-0.13 and 3.52+/-0.41 mg/dL, before and after LPS, respectively) was significantly inhibited by a pre-treatment with prednisolone (1.39+/-0.32 mg/dL, p<0.01) and attenuated (2.65+/-0.30 mg/dL, p=0.09) with cilomilast.
  
  
  CONCLUSIONS
  In healthy subjects, while the LPS-induced airways' inflammation was not modified either by oral prednisolone or by PDE-4 inhibitor cilomilast (at actual dosage), the LPS-induced acute phase of blood inflammation was reduced by prednisolone.
authors.affiliation: Clinics of Allergology and Respiratory Diseases, CHU Saint-Pierre (ULB-CP404), Rue Haute 322, B-1000 Brussels, Belgium. omichel@ulb.ac.be
authors.forename: Olivier
authors.initials: O
authors.lastname: Michel
authors.forename: Mieke
authors.initials: M
authors.lastname: Dentener
authors.forename: Didier
authors.initials: D
authors.lastname: Cataldo
authors.forename: Brigitte
authors.initials: B
authors.lastname: Cantinieaux
authors.forename: Françoise
authors.initials: F
authors.lastname: Vertongen
authors.forename: Catherine
authors.initials: C
authors.lastname: Delvaux
authors.forename: Robert D
authors.initials: RD
authors.lastname: Murdoch
mesh_terms: D000208:Acute Disease; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002097:C-Reactive Protein / Q000378:metabolism; D002264:Carboxylic Acids / Q000494:pharmacology; D018592:Cross-Over Studies; D003509:Cyclohexanecarboxylic Acids; D004311:Double-Blind Method; D019040:E-Selectin / Q000378:metabolism; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011239:Prednisolone / Q000494:pharmacology*; D013183:Sputum / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D002264:Carboxylic Acids; D003509:Cyclohexanecarboxylic Acids; D019040:E-Selectin; D005938:Glucocorticoids; D008070:Lipopolysaccharides; D009570:Nitriles; D010726:Phosphodiesterase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; C433247:Cilomilast; D002097:C-Reactive Protein; D011239:Prednisolone; D020780:Matrix Metalloproteinase 9