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-a (TNF-a) release from monocytes was measured by ELISA and anti-IgE stimulated histamine release from mast cells was measured by a radioenzymatic method. 4 The fl2 agonist, salbutamol inhibited TNF-a 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-a 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-ax 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-a 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 fl2 agonists, corticosteroids and PDE inhibitors are distinct.

Selective phosphodiesterase inhibitors modulate the activity of alveolar macrophages from sensitized guinea-pigs

“…The release of arachidonate was significantly reduced upon oral treatment of the guinea-pigs by the selective PDE4 inhibitors rolipram and Ro 20-1724, but not by the selective PDE3 inhibitor milrinone. In agreement with a previous study on the reduced activity of guinea-pig alveolar macrophages by PDE4 inhibitors [30], the present data confirm the potential interest of selective PDE4 inhibitors as anti-inflammatory drugs. It was previously demonstrated that, at the same doses, rolipram and Ro 20-1724 significantly reduced the recruitment of eosinophils in guinea-pigs induced by OA challenge, platelet-activating factor or interleukin-5 [16,31].…”

The effects of phosphodiesterase type 4 inhibitors on tumour necrosis factor‐α and leukotriene B4 in a novel human whole blood assay

“…PDE III-selective inhibitors have shown inhibitory activity on monocyte-derived TNF-a production and on neutrophil-derived leukotriene production (Banner et al, 1996;Schudt et al, 1991). In our assay, the PDE III-selective inhibitors were also active but to a lesser extent than the PDE4 inhibitors.…”

Effect of the Mixed Phosphodiesterase 3/4 Inhibitor RPL554 on Human Isolated Bronchial Smooth Muscle Tone

“…Whereas PDE4 inhibitors are efficacious inhibitors of proinflammatory mediator release from certain cell types, there is evidence to suggest that dual inhibition of PDE3 and PDE4 is additive or synergistic at suppressing the activation/ functions of other cell types (e.g., macrophages, dendritic cells, epithelial cells, lymphocytes, and endothelial cells) (Banner et al, 1996;Giembycz et al, 1996;Blease et al, 1998;Wright et al, 1998;Gantner et al, 1999;Hatzelmann and Schudt, 2001;Banner and Press, 2009) but are not effective at relaxing ASM in vitro and do not cause acute bronchodilation experimentally (Boswell-Smith et al, 2006a) or clinically (Grootendorst et al, 2003). In contrast, PDE3 inhibitors are able to relax human ASM (Matera et al, 2011b) and can elicit bronchodilation in humans (Myou et al, 1999(Myou et al, , 2003.…”