Inhibition of eosinophil activation in bronchoalveolar lavage fluid from atopic asthmatics by Y-24180, an antagonist to platelet-activating factor

Mizuki, Masami; Komatsu, Hidetada; Akiyama, Youichi; Iwane, Shuichi; Tsuda, Toshihide

doi:10.1016/s0024-3205(99)00470-1

Cited by 9 publications

(7 citation statements)

References 17 publications

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“…BAL-AH activity in patients with mild bronchial asthma was significantly lower than that in normal donors, How may PAF contribute to the pathogenesis of asthma and how it behavior in asthmatics? PAF receptor mRNA levels were significantly increased in eosinophils and in the lungs of asthmatics [10,11] PAF-induced histamine release and basophils activation may be relevant in the pathogenesis of aspirin-induced asthma [14] PAF-induced eosinophil chemotaxis increased during asthmatic attacks and was inhibited by steroids [21] PAF was able to enhance LTC4 formation by stimulated eosinophils obtained from asthmatic patients [25] PAF enhanced LTB4 release and increased 5-LO activity from stimulated neutrophils from asthmatics [28] PAF increased expression of matrix metalloproteinase-9 which may be actively involved in remodeling [33] Granulocytes from asthmatics showed significantly higher PAF generation [46] Remarkable increase in plasma PAF level was found in patients with seasonal asthma following allergen-induced bronchoconstriction level, chronic asthma, and during acute asthmatic attacks [35,37,38,40] The increased production of PAF decreased to normal following successful allergen immunotherapy [37] Increased concentration of PAF was found in BAL fluid from asthmatic patients [39] Lower serum and BAL level of PAF-AH, an enzyme that specifically inactivates PAF activity was observed in asthmatics [40,73] PAF administration can mimic some of the abnormalities observed in asthma, including bronchoconstriction, bronchial hyperresponsiveness, inflammatory infiltration, mucus hypersecretion, vascular leakage and gas exchange impairment [41-45, 50-53-55] Zileuton, a 5-LO inhibitor, effectively attenuated all systemic and respiratory effects promoted by inhaled PAF [51,63] PAF-AH gene may be a modulating locus for the severity of asthma [71] The most common loss-of-function mutation (V279F) in the PAF-AH gene itself is not any predisposing factor of atopy, asthma, or asthma severity in Japanese adult population [72] Effects of PAF receptor antagonists in asthma Y-24180 was able to inhibit eosinophil activation in bronchoalveolar lavage fluid from atopic asthmatics [27] Y-24180 improved the PC20-FEV1 value in patients with asthma [76] SR27417 had a modest inhibitory effect on LAR and showed no effects upon EAR, allergen-induced airway responsiveness [80] The randomized controlled trials of PAF a...…”

Section: The Role Of Paf-ah In Asthmamentioning

confidence: 99%

“…WEB 2086, a selective PAF receptor antagonist inhibited eosinophil chemotaxis and LTC4 production from these cells [26]. Another PAF antagonist, Y-24180 is able to inhibit eosinophil activation in bronchoalveolar lavage fluid from atopic asthmatics [27]. In stimulated neutrophils from asthmatic patients, PAF enhanced leukotriene B4 (LTB4) release and increased 5-lipoxygenase (5-LO) activity and intracellular calcium to a greater extent than in neutrophils from non-asthmatic patients [28].…”

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confidence: 99%

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Platelet Activating Factor as a Mediator and Therapeutic Approach in Bronchial Asthma

2008

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Platelet activating factor (PAF) is a potent phospholipid mediator involved in anaphylaxis and chronic inflammatory disorders, including bronchial asthma. PAF is able to act both, directly as a chemotactic factor and indirectly through the release of other inflammatory agents. Apart from its known potent ability to activate platelets, PAF influences other immune and inflammatory cells function involved in asthma, which may be of importance in the pathogenesis of the disease. In addition, PAF administration can mimic some of abnormalities observed in asthma, including bronchoconstriction, bronchial hyper responsiveness, and gas exchange impairment, which may be mediated by leukotrienes acting as secondary mediators of some PAF effects. Therefore, there has been an extensive interest in the role of PAF in human asthma and major efforts have been continued to discover drugs acting thorough inhibition of PAF effects in the disease. Surprisingly, PAF receptor antagonists have not clearly proven their clinical benefits. It may appear that the combined blockage of PAF effects and other mediators involved in asthma is a way to improve clinical efficacy and also an interesting approach to control inflammation in the disease. This review will focus on two main issues: the role of PAF and PAF antagonists in asthma.

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Section: The Role Of Paf-ah In Asthmamentioning

confidence: 99%

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confidence: 99%

Platelet Activating Factor as a Mediator and Therapeutic Approach in Bronchial Asthma

2008

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“…In epidemiologic studies a lack of PAF acetylhydrolase, which catalyzes hydrolysis of PAF, was associated with atopy and severe asthma [29, 30]. While a recent clinical study demonstrated that administration of a new, long-acting PAF receptor antagonist to patients with atopic asthma effectively inhibited eosinophilic inflammation in the airways [31], other clinical studies in patients with asthma found no significant efficacy for PAF receptor antagonists [32]. Thus, further studies are needed to elucidate how PAF contributes to human asthma.…”

Section: Introductionmentioning

confidence: 99%

Dual Signaling and Effector Pathways Mediate Human Eosinophil Activation by Platelet-Activating Factor

Katô¹,

Kita²,

Tachibana³

et al. 2004

Int Arch Allergy Immunol

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Platelet-activating factor (PAF) induces various cellular functions in eosinophils including chemotaxis, adhesion, superoxide anion (O₂^–) production, and degranulation. While PAF shares many biological effects with other chemotactic factors such as N-formyl-methionyl-leucyl-phenylalanine, complement fragments, and lipid mediators, PAF is unique in that its action is relatively resistant to pertussis toxin (PTX), and in activating eosinophils more strongly than neutrophils. In this review we consider how PAF might activate human eosinophils in preference to neutrophils, and discuss possible mechanisms of PAF-induced activation of human eosinophils via two distinct signaling and effector pathways. Recently we analyzed O₂^– production by eosinophils using a sensitive, real-time chemiluminescence method. Our results showed that in human eosinophils PAF activates two distinct signaling and effector pathways coupled to the PAF receptor: one linked to PTX-sensitive G protein(s) and another to PTX-resistant G protein(s), phosphatidylinositol 3-kinase, and cellular adhesion. This activation of two different G proteins by the eosinophil PAF receptor may explain the strong and diverse biological responses of human eosinophils to PAF.

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“…For instance, mice deficient in the PAF receptor do not manifest any acute allergic airway reactions to ovalbumin [3]and a new PAF receptor antagonist efficiently inhibits eosinophilic airway inflammation in patients with bronchial asthma [4]. In addition, the lack of PAF acetylhydrolase, which catalyzes the hydrolysis of PAF, has been shown to be associated with atopy and asthma [5, 6].…”

Section: Introductionmentioning

confidence: 99%

Distinct Isoforms of Protein Kinase C Are Involved in Human Eosinophil Functions Induced by Platelet-Activating Factor

Takizawa

Katô

Suzuki

et al. 2003

Int Arch Allergy Immunol

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Background: Platelet-activating factor (PAF) is a potent stimulator of eosinophils. Recently, treatment with a protein kinase C (PKC) inhibitor which generally inhibits PKC isoforms has been shown to modulate several eosinophil functions in distinct manners, in that PKC inhibition enhanced CD11b expression and cellular adhesion, but inhibited superoxide generation and degranulation in PAF-stimulated human eosinophils. These results suggested that distinct PKC isoforms were likely to be involved in each eosinophil function induced by PAF. We have therefore investigated whether or not the PKC isoforms involved in PAF-induced CD11b expression and superoxide generation were different. Methods: Human eosinophils prepared from healthy volunteers were treated with PKC inhibitors, bis-indolylmaleimide I (BisI; a general PKC inhibitor), myristoylated PKC inhibitor peptide (myr-ψPKC; a PKCα, β and δ inhibitor) and rottlerin (a PKCδ inhibitor), followed by stimulation with PAF. CD11b expression was determined using flow cytometry and superoxide generation was evaluated using a cytochrome c reduction assay. Results: BisI treatment led to enhancement of PAF-induced CD11b expression, while myr-ψPKC and rottlerin did not. In contrast, PAF-induced superoxide generation was inhibited by treatment with BisI, myr-ψPKC and rottlerin. Conclusions: PKCα, β and δ are not involved in PAF-induced CD11b expression, but PKCδ is involved in the PAF-induced activation of superoxide anion generation.

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Inhibition of eosinophil activation in bronchoalveolar lavage fluid from atopic asthmatics by Y-24180, an antagonist to platelet-activating factor

Cited by 9 publications

References 17 publications

Platelet Activating Factor as a Mediator and Therapeutic Approach in Bronchial Asthma

Platelet Activating Factor as a Mediator and Therapeutic Approach in Bronchial Asthma

Dual Signaling and Effector Pathways Mediate Human Eosinophil Activation by Platelet-Activating Factor

Distinct Isoforms of Protein Kinase C Are Involved in Human Eosinophil Functions Induced by Platelet-Activating Factor

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