Selective Phosphodiesterase Type 4 Inhibitors Reduce the Prolonged Survival of Eosinophils Stimulated by Granulocyte-Macrophage Colony-Stimulating Factor.

Takeuchi, Masayuki; Tatsumi, Yasuaki; Kitaichi, Kiyoyuki; Baba, Kenji; Suzuki, Ritsuro; Shibata, Eiji; Takagi, Kenji; Miyamoto, Ken‐ichi; Hasegawa, Takaaki; Takagi, Kenzo

doi:10.1248/bpb.25.184

Cited by 11 publications

(10 citation statements)

References 26 publications

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“…19) The concentration of GM-CSF used in our study, which was the same as in a previous report showing the inhibitory effect of rolipram on the survival rate of eosinophils cultured with GM-CSF, 24) was within the range of 10 to 200 pg/ml observed in sputum and in bronchoalveolar lavage fluid from asymptomatic and symptomatic asthmatics or from mild asthmatics after allergen challenge.…”

Section: Discussionsupporting

confidence: 59%

“…Although PDE 4 inhibitors including rolipram have been reported to reduce eosinophil survival prolonged by culture with IL-5 or GM-CSF, 23,24) whether the reduction is due to the induction of apoptosis had not been investigated. The increased apoptosis in cells of eosinophil lineage due to theophylline and specific PDE 4 inhibitors was reported only in circulating progenitor cells from asthmatics.…”

Section: Discussionmentioning

confidence: 99%

“…[19][20][21][22][23][24] Together with the pathogenic roles of eosinophils in asthma, there has been increased interest in the therapeutic benefit of these agents in asthma. However, the mechanisms by which PDE 4 inhibitors suppress eosinophil survival remain to be elucidated, 23,24) while theophylline and d-cAMP were shown to decrease the survival rate via the induction of apoptosis. [19][20][21][22] Therefore, to evaluate whether PDE 4 inhibitors have the ability to cause eosinophils to undergo apoptosis, we examined the effects of selective PDE isoenzyme inhibitors on eosinophil survival proloned by GM-CSF.…”

mentioning

confidence: 99%

“…14,16,18) Furthermore, PDE 4 inhibitors and theophylline, as well dibutyryl cAMP (d-cAMP), a cAMP analogue, have been also demonstrated to reduce eosinophil survival prolonged by GM-CSF or IL-5. [19][20][21][22][23][24] Together with the pathogenic roles of eosinophils in asthma, there has been increased interest in the therapeutic benefit of these agents in asthma. However, the mechanisms by which PDE 4 inhibitors suppress eosinophil survival remain to be elucidated, 23,24) while theophylline and d-cAMP were shown to decrease the survival rate via the induction of apoptosis.…”

mentioning

confidence: 99%

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Inhibition of Eosinophil Survival by a Selective Inhibitor of Phosphodiesterase 4 via the Induction of Apoptosis

Wang

Masu

Tamura

et al. 2005

Biological & Pharmaceutical Bulletin

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Bronchial asthma is a disease characterized by chronic airway inflammation associated with the accumulation and activation of inflammatory cells, such as eosinophils, in the bronchial wall and airway lumen. Eosinophils at the site of inflammation release preformed and newly synthesized mediators, including eosinophil cationic protein, major basic protein, leukotriene C 4 , and reactive oxygen. These mediators contribute to the formation of the pathological features of asthmatic airways such as bronchoconstriction, mucus hypersecretion, microvascular leakage, submucosal edema, and epithelial shedding, which lead to the clinical features of asthma, hyperresponsiveness, and airway narrowing. [1][2][3][4][5] Eosinophils cultured in the absence of hematopoietic cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-5 undergo apoptosis, which is physiologic cell death characterized by morphologic changes such as membrane blebbing and nuclear condensation, and by the degradation of DNA into oligonucleosomesized fragments showing a "ladder" pattern on agarose gel. [6][7][8] Apoptotic eosinophils have been shown to be removed from the tissue without releasing inflammatory mediators after ingestion by macrophages, 8) which is believed to be one of the important mechanisms in the resolution of inflammation.9) GM-CSF and IL-5, which have been detected in sputum, bronchoalveolar lavage fluid, and bronchial tissues from asthmatics, 5) prolong the survival of tissue eosinophils through the prevention of apoptosis, 10,11) leading to the development and maintenance of airway inflammation. Therefore the induction of apoptosis in eosinophils would be beneficial in the treatment of asthma. The induction of apoptosis in airway eosinophils by the administration of anti-Fas antibody or inhaled steroid is reported to be associated with the reduction or termination of asthmatic airway inflammation in vivo. 12,13) cAMP is well known as a second messenger mediating intracellular signal transduction evoked by the binding of agonists to their cell-surface receptors. The concentration of intracellular cAMP is dependent on the catalysis rate of ATP to cAMP by adenylate cyclase and of cAMP to 5Ј-adenosine monophosphate by cyclic nucleotide phosphodiesterases (PDEs).14) PDEs comprise at lease 11 families containing, in total, more than 50 different PDE enzyme variants, the differentiation of which is based on the primary protein and cDNA sequences, substrate specificity, regulation of enzymatic activity, and calcium/calmodulin dependence.15) The increased concentration of intracellular cAMP is known to suppress the functions of inflammatory cells.14,16) With regard to eosinophils of which the PDE isoenzyme is exclusively type 4, 17) selective inhibitors of PDE 4 and theophylline, a nonselective PDE inhibitor, have been shown to inhibit chemotaxis, adhesion, degranulation, and the release of active oxygen by an increase in the cAMP content.14,16,18) Furthermore, PDE 4 inhibitors and theophylline, as well...

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of Eosinophil Survival by a Selective Inhibitor of Phosphodiesterase 4 via the Induction of Apoptosis

Wang

Masu

Tamura

et al. 2005

Biological & Pharmaceutical Bulletin

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“…Pertussis toxin (PTX) was obtained from Calbiochem (San Diego, Calif., USA). The concentrations of these reagents were based on previous studies [27,28,29]. …”

Section: Methodsmentioning

confidence: 99%

Differential Activation of Eosinophils by ‘Probiotic’ <i>Bifidobacterium bifidum</i> and ‘Pathogenic’ <i>Clostridium difficile</i>

Hosoki

Nakamura²,

Nagao³

et al. 2010

Int Arch Allergy Immunol

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Background: Recent studies suggest that probiotics alleviate pathophysiological processes of allergic diseases and inflammatory bowel diseases, whereas ‘non-probiotic’ microflora has negative effects. However, the underlying mechanisms are not well known, especially in relation to eosinophils, the major effector cells of these inflammatory diseases. Objective: To investigate the effects of probiotic Bifidobacterium bifidum (BB) on human eosinophil functions compared with pathogenic Clostridium difficile (CD). Methods: Peripheral human eosinophils were cultured with heat-killed BB or CD. FISH-labeled CD and BB were incubated with eosinophils visualized by confocal laser scanning microscopy. Superoxide generation and degranulation of eosinophils were measured with the cytochrome c reduction method and the eosinophil-derived neurotoxin (EDN) release assay, respectively. Results: Confocal microscopy revealed that Cy3-labeled CD and BB were apparently ingested by eosinophils. Both bacteria induced minimal superoxide generation. However, CD elicited significantly higher EDN release than BB. GM-CSF significantly enhanced EDN release by CD but not by BB. Bacterial-induced EDN release was calcium dependent. Conclusion: The beneficial effect of probiotic BB might be explained, at least in part, by its ability to decrease EDN release from eosinophils compared with ‘pathogenic’ CD.

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Xanthines and Phosphodiesterase Inhibitors

Spina

Page

2016

Handbook of Experimental Pharmacology

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Theophylline is an orally acting xanthine that has been used since 1937 for the treatment of respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, in most treatment guidelines, xanthines have now been consigned to third-line therapy because of their narrow therapeutic window and propensity for drug-drug interactions. However, lower than conventional doses of theophylline considered to be bronchodilator are now known to have anti-inflammatory actions of relevance to the treatment of respiratory disease. The molecular mechanism(s) of action of theophylline are not well understood, but several potential targets have been suggested including non-selective inhibition of phosphodiesterases (PDE), inhibition of phosphoinositide 3-kinase, adenosine receptor antagonism and increased activity of certain histone deacetylases. Although theophylline has a narrow therapeutic window, other xanthines are in clinical use that are claimed to have a better tolerability such as doxofylline and bamifylline. Nonetheless, xanthines still play an important role in the treatment of asthma and COPD as they can show clinical benefit in patients who are refractory to glucocorticosteroid therapy, and withdrawal of xanthines from patients causes worsening of disease, even in patients taking concomitant glucocorticosteroids.More recently the orally active selective PDE4 inhibitor, roflumilast, has been introduced into clinical practice for the treatment of severe COPD on top of gold standard treatment. This drug has been shown to improve lung function in patients with severe COPD and to reduce exacerbations, but is dose limited by a range side effect, particularly gastrointestinal side effects.

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Selective Phosphodiesterase Type 4 Inhibitors Reduce the Prolonged Survival of Eosinophils Stimulated by Granulocyte-Macrophage Colony-Stimulating Factor.

Cited by 11 publications

References 26 publications

Inhibition of Eosinophil Survival by a Selective Inhibitor of Phosphodiesterase 4 via the Induction of Apoptosis

Inhibition of Eosinophil Survival by a Selective Inhibitor of Phosphodiesterase 4 via the Induction of Apoptosis

Differential Activation of Eosinophils by ‘Probiotic’ <i>Bifidobacterium bifidum</i> and ‘Pathogenic’ <i>Clostridium difficile</i>

Xanthines and Phosphodiesterase Inhibitors

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