title: The effect of selective phosphodiesterase 3 and 4 isoenzyme inhibitors and established anti-asthma drugs on inflammatory cell activation.
abstract: 1. This study aimed to evaluate the effects of phosphodiesterase (PDE) inhibitors and currently prescribed anti-asthma drugs for their ability to inhibit inflammatory cell activation in vitro. 2. Alveolar macrophages and eosinophils were isolated from the bronchoalveolar lavage (BAL) fluid of ovalbumin (Ovalb)-sensitized guinea-pigs. Opsonized zymosan (OZ) and PAF stimulated leukotriene B4 (LTB4) release from eosinophils was measured by radioimmunoassay. Ovalb-induced superoxide generation was measured by reduction of cytochrome C. 3. Monocytes were separated from human peripheral venous blood and mast cells were dispersed from human lung fragments. Lipopolysaccharide (LPS)-induced tumour necrosis factor-alpha (TNF-alpha) release from monocytes was measured by ELISA and anti-IgE stimulated histamine release from mast cells was measured by a radioenzymatic method. 4. The beta 2 agonist, salbutamol inhibited TNF-alpha release from monocytes and histamine release from mast cells whilst having no effect on eosinophil-derived LTB4 release or macrophage superoxide generation. 5. The PDE 3 inhibitor, milrinone produced a concentration-related inhibition of TNF-alpha release from monocytes which achieved statistical significance at 10(-5) M but inhibited LTB4 release from eosinophils and superoxide generation from macrophages only at the highest concentration (10(-3) M) examined. Milrinone had no effect on histamine release from mast cells. 6. The selective PDE 4 inhibitors, denbufylline and rolipram and the corticosteroid, beclomethasone produced a concentration-related inhibition of LTB4 release from eosinophils, TNF-alpha release from monocytes and superoxide generation from alveolar macrophages whilst having no effect on histamine release from mast cells. 7. The mixed PDE 3/4 inhibitor, benzafentrine produced a concentration-related inhibition of LTB4 release from eosinophils, TNF-alpha release from monocytes, superoxide generation from alveolar macrophages and histamine release from mast cells. 8. In conclusion these data clearly show that both established anti-asthma medication as well as PDE inhibitors have the potential to inhibit inflammatory cell activation in vitro but that the anti-secretory actions of beta 2 agonists, corticosteroids and PDE inhibitors are distinct.
authors.affiliation: Department of Pharmacology, King's College London.
authors.forename: K H
authors.initials: KH
authors.lastname: Banner
authors.forename: E
authors.initials: E
authors.lastname: Moriggi
authors.forename: B
authors.initials: B
authors.lastname: Da Ros
authors.forename: G
authors.initials: G
authors.lastname: Schioppacassi
authors.forename: C
authors.initials: C
authors.lastname: Semeraro
authors.forename: C P
authors.initials: CP
authors.lastname: Page
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001792:Blood Platelets / Q000201:enzymology; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D006636:Histamine Release; D006801:Humans; D007527:Isoenzymes / Q000032:analysis / Q000037:antagonists & inhibitors*; D007975:Leukotriene B4 / Q000096:biosynthesis; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects; D009504:Neutrophils / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000032:analysis; D013481:Superoxides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018927:Anti-Asthmatic Agents; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D007975:Leukotriene B4; D010727:Phosphoric Diester Hydrolases