title: Tumour necrosis factor-alpha production in human alveolar macrophages: modulation by inhaled corticosteroid.
abstract: Using an ex vivo alveolar macrophage model, the hypothesis that inhaled preparations of corticosteroids might have important anti-inflammatory effects on cells of the peripheral airway was tested. The tumour necrosis factor (TNF)-alpha-inducing potential of three glycolipid preparations from nonpathogenic (arabinofuranasyl lipoarabinomannan (LAM (Ara-LAM)) and virulent (mannase LAM (ManLAM)) mycobacteria and Gram-negative bacteria (lipopolysaccharide (LPS)), in primary alveolar macrophage preparations was investigated. A novel inhaled chlorofluorocarbon (CFC)-free preparation of beclomethasone dipropionate (hydrofluoroalkane 134a (HFA)-BDP) with increased peripheral lung deposition was investigated for its ability to modulate glycolipidinduced TNF-alpha production by human alveolar macrophages, in comparison with a CFC-containing preparation and placebo. Compared to the basal TNF-alpha bioactivity of 0.72 ng x mL-1 (geometric mean), the TNF-alpha bioactivity in the macrophage preparation increased following incubation with LPS (138 ng x mL-1, p<0.001), AraLAM (12.6 ng-mL-1, p<0.001) and ManLAM (1.42 ng x mL-1, p=0.02). HFA-BDP, administered in vivo, significantly reduced LPS- and ManLAM-induced TNF-alpha production by alveolar macrophages cultured ex vivo. No change in glycolipid-induced TNF-alpha production was observed following in vivo administration of CFC-BDP or HFA-placebo. This is the first demonstration of an immunomodulatory effect on alveolar cells of corticosteroid delivered via metered dose inhaler. The present findings suggest that alveolar deposition of beclomethasone dipropionate is capable of modulating the inflammatory potential of the alveolar macrophage population.
authors.affiliation: Dept of Respiratory Medicine, National Heart and Lung Institute, Imperial College School of Medicine, London, UK.
authors.forename: B G
authors.initials: BG
authors.lastname: Marshall
authors.forename: A
authors.initials: A
authors.lastname: Wangoo
authors.forename: L I
authors.initials: LI
authors.lastname: Harrison
authors.forename: D B
authors.initials: DB
authors.lastname: Young
authors.forename: R J
authors.initials: RJ
authors.lastname: Shaw
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D001507:Beclomethasone / Q000008:administration & dosage*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology*; D001999:Bronchoscopy; D002478:Cells, Cultured; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage*; D006801:Humans; D016014:Linear Models; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D012680:Sensitivity and Specificity; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000187:drug effects*
chemical_list: D005938:Glucocorticoids; D014409:Tumor Necrosis Factor-alpha; D001507:Beclomethasone