Effects of selective phosphodiesterase inhibitors on the polymorphonuclear leukocyte respiratory burst1

Nielson, Christopher; Vestal, Robert E.; Sturm, Robert J.; Heaslip, Richard J.

doi:10.1016/s0091-6749(05)80186-1

Cited by 167 publications

(92 citation statements)

References 30 publications

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“…Differences were accepted as significant when P < 0 : 05. IC 50 and EC 50 were calculated by regression analysis of percent inhibition data [7]. (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Other than causing tissue injury, neutrophil oxidants are presently thought to be involved in the pathogenesis of airway hyperreactivity and/ or bronchoconstriction [5,6]. As in other neutrophilic inflammatory processes, the extent of the neutrophil activation and, in turn, the generation of oxidants are down-regulated by endogenous mediators, mainly circulating catecholamines [7,8] and locally produced prostaglandins such as PGE 2 [9], via augmentation of intracellular levels of cyclic AMP (cAMP). Moreover, compounds endowed with phosphodiesterase IV (PDE-IV) inhibitory activity are able to down-regulate activated neutrophils' oxidant generation by elevating intracellular cAMP levels [10,11].…”

Section: Introductionmentioning

confidence: 99%

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Inhibitory effect of salmeterol on the respiratory burst of adherent human neutrophils

Ottonello

Morone

Dapino

et al. 1996

Clinical and Experimental Immunology

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SUMMARYHuman neutrophils, plated in fibronectin-coated wells and stimulated with N-formyl-methionyl-leucylphenylalanine (fMLP), were found to undergo a massive and prolonged respiratory burst, as measured by monitoring superoxide production. The 2 -agonist salmeterol inhibited the respiratory burst in a dose-dependent manner. In contrast, salbutamol was ineffective. Moreover, the neutrophil respiratory burst was partially suppressed by prostaglandin E 2 (PGE 2 ) and the phosphodiesterase type IV (PDE-IV) inhibitor RO 20-1724. When salmeterol was used in combination with PGE 2 or RO 20-1724, additive inhibitory effects were observed. The inhibitory activity of salmeterol was not reversed in the presence of the -blocker propranolol, and did not correlate with its ability of increasing cyclic AMP (cAMP) levels. Finally, the compounds used did not affect neutrophil adherence to fibronectin-coated wells. The results suggest that salmeterol is capable of down-regulating the neutrophil oxidative response to fMLP, also of co-operating with PGE 2 and PDE-IV inhibitor RO 20-1724 in a manner not related to its 2 -receptor binding activity. In other words, salmeterol displays neutrophil-directed effects, susceptible to be amplified by natural mediators such as PGE 2 or PDE-IV inhibitors, consistent with possible anti-inflammatory properties of the drug.

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“…Differences were accepted as significant when P < 0 : 05. IC 50 and EC 50 were calculated by regression analysis of percent inhibition data [7]. (Fig.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibitory effect of salmeterol on the respiratory burst of adherent human neutrophils

Ottonello

Morone

Dapino

et al. 1996

Clinical and Experimental Immunology

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“…This is of interest for substances to be used in the treatment of asthma and goes side by side with other specific and potentially interesting effects of PDE type IV inhibitors, such as inhibition of the microvascular leakage induced by PAF in the guinea-pig (Raeburn & Karlson, 1992;Ortiz et al, 1992), of the N-formylmethionylleucyl-phenylalanine (fMLP)-stimulated superoxide release and fMLP/thiomerosal elicited leukotriene biosynthesis by human polymorphonuclear leukocytes (Schudt et al, 1991), as well as inhibition of mediator release from human basophils, mast cells, monocytes or neutrophils (Peachell et al, 1990;Neilson et al, 1990) or of superoxide formation in guinea-pig eosinophils (Dent et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Effects of rolipram and siguazodan on the human isolated bronchus and their interaction with isoprenaline and sodium nitroprusside

Qian¹,

Naline²,

Karlsson³

et al. 1993

British J Pharmacology

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1 The effects of the selective inhibitors of cyclic AMP phosphodiesterase type IV (rolipram) and type III (siguazodan) and their interactions with isoprenaline and sodium nitroprusside have been studied in the human isolated bronchus. 2 On bronchi under resting tone rolipram was, in terms of potency (pD2 = 7.77 ± 0.14, n = 8), very similar to isoprenaline (pD2 = 7.31 ± 0.12, n = 12) and salbutamol (pD2 = 7.12 ± 0.17, n = 10) and approximately 10 fold more potent than siguazodan (pD2 = 6.80 ± 0.12, n = 6). In terms of efficacy (Ema,x expressed as percentage of maximal effect induced by theophylline 3 mM), both rolipram and siguazodan were less efficient (Emax = 74 ± 6.7%, n = 8 and 66 ± 7.5%, n = 6, respectively) than isoprenaline (Emax = 98 ± 0.4%, n = 12) and salbutamol (Emax = 83 + 2.4%, n = 10).3 During precontraction induced by methacholine (3 x 10-M) or acetylcholine (10-3 M), concentration-response curves to rolipram and siguazodan were shifted to the right and maximal effects reduced. Rolipram was more potent than siguazodan and, in terms of efficacy, it was less active. 4 Rolipram 10-8 and 10-M but not siguazodan potentiated the effects of isoprenaline as shown by the shift to the left of the concentration-response curve to isoprenaline. Sodium nitroprusside-induced relaxation was not modified by either drug. 5 These results show that rolipram is a potent relaxant of the human isolated bronchus, potentiating the effects of P-adrenoceptor stimulation and suggest that, as previously demonstrated in other species (guinea-pig, cow) (Tomkinson et al., 1993), there may be a connection between the P2-adrenoceptor subtype, which predominate in human airway smooth muscle, and the cyclic AMP phosphodiesterase type IV.

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“…Inhibition of this enzyme leads to increases in intracellular cyclic AMP which can subsequently activate protein kinase A (PKA) (Torphy & Undem, 1991;Seldon et al, 1995). It has been shown with various PDE4-speci®c inhibitors that an increase in intracellular cyclic AMP can inhibit the expression and release of several in¯ammatory mediators, prevent superoxide anion formation in neutrophils, inhibit eosinophil chemotaxis and degranulation as well as lymphocyte proliferation, and causes relaxation of bronchial smooth muscles resulting in bronchodilatation (Nielson et al, 1990;Hartman et al, 1993;Underwood et al, 1994;Schudt et al, 1995;Essayan et al, 1997). PDE4 is predominantly expressed in monocytes, neutrophils and eosinophils (Schudt et al, 1995) and its inhibition could be bene®cial in treating the underlying in¯ammation associated with asthma.…”

Section: Introductionmentioning

confidence: 99%

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

Brideau

Staden

Styhler

et al. 1999

British J Pharmacology

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1 The aim of this study was to assess the inhibitory activities of phosphodiesterase type 4 (PDE4) inhibitors on tumour necrosis factor-a (TNF-a) and leukotriene B 4 (LTB 4 ) production in a novel human whole blood assay. 2 Lipopolysaccharide (LPS) stimulation of human whole blood caused a time dependent increase in TNF-a and prostaglandin E 2 (PGE 2 ) plasma levels. Inhibition of LPS-induced TNF-a by the selective PDE4 inhibitor RP73401 was proportionally enhanced with endogenous PGE 2 (maximal after 24 h). In contrast, blocking endogenous PGE 2 production with indomethacin in blood stimulated with LPS for 24 h decreased the potency of RP73401 to that observed with a 4 h LPS incubation. 3 Non-selective and selective PDE4 inhibitors showed greater inhibition of LPS-induced TNF-a after 24 h compared to 4 h. Stereoselectivity was only achieved in the 24 h method. 4 LPS-stimulation of whole blood for either 30 min or 24 h followed by N-formyl-Met-Leu-Phe (fMLP) activation resulted in low plasma LTB 4 levels. Combination of both treatments resulted in a greater than 7 fold increase in plasma LTB 4 levels. Inhibition of the double LPS and fMLP-activated LTB 4 production was observed with non-selective and PDE4-selective inhibitors. Their LTB 4 inhibitory potencies were similar to that observed in the 24 h LPS-induced TNF-a assay. Thus, stimulation of human whole blood with two LPS stimulations followed by fMLP gives rise to both TNF-a and LTB 4 and their inhibition by various compounds can be assessed in the same blood sample. 5 Calcium ionophore (A23187) stimulation of whole blood resulted in plasma LTB 4 levels similar to the double LPS and fMLP method. Inhibition of A23187-induced LTB 4 biosynthesis was also achieved by PDE4-selective inhibitors as well as the direct 5-lipoxygenase (5-LO) inhibitor L-739,010. 6 These results con®rm the anti-in¯ammatory properties of PDE4 inhibitors. Thus, this novel human whole blood can be used to assess the biochemical e cacy of PDE4 inhibitors in human subjects.

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Effects of selective phosphodiesterase inhibitors on the polymorphonuclear leukocyte respiratory burst1

Cited by 167 publications

References 30 publications

Inhibitory effect of salmeterol on the respiratory burst of adherent human neutrophils

Inhibitory effect of salmeterol on the respiratory burst of adherent human neutrophils

Effects of rolipram and siguazodan on the human isolated bronchus and their interaction with isoprenaline and sodium nitroprusside

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

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Effects of selective phosphodiesterase inhibitors on the polymorphonuclear leukocyte respiratory burst1

Cited by 167 publications

References 30 publications

Inhibitory effect of salmeterol on the respiratory burst of adherent human neutrophils

Inhibitory effect of salmeterol on the respiratory burst of adherent human neutrophils

Effects of rolipram and siguazodan on the human isolated bronchus and their interaction with isoprenaline and sodium nitroprusside

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

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