Platelet Activating Factor: Effects on Bronchomotor Tone and Bronchial Responsiveness in Human Beings

Kf, Chung; Fm, Cuss; Barnes, Peter J.

doi:10.2500/108854189778959885

Cited by 6 publications

(6 citation statements)

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“…Platelet-activating factor can play a central role in the propagation of chronic inflammatory conditions by increasing systemic, pulmonary, and microvascular permeability and disrupting vascular integrity . Additionally, PAF stimulates migration of eosinophils into the airways and induces airway smooth muscle contraction and hyperreactivity in otherwise healthy subjects , . Increased numbers of eosinophils in airway secretions are a characteristic feature of asthma and are associated with disease severity , .…”

Section: Discussionmentioning

confidence: 99%

“…We have previously demonstrated that stimulation of human pulmonary vascular endothelial cells (HMVEC-L) with thrombin and tryptase activates calcium-independent phospholipase A 2 (iPLA 2 ), which results in increased arachidonic acid release and production of prostaglandin I 2 (PGI 2 ) and platelet-activating factor (PAF) . PAF induces bronchoconstriction, bronchial hyperresponsiveness, inflammatory infiltration, mucus hypersecretion, and impaired gas exchange, and this contributes to the pathogenesis of bronchial asthma , . Additionally, PAF associated with endothelial cells assists in the tethering and transendothelial migration of circulating inflammatory cells, and this results in increased pulmonary microvascular permeability and sequestration of neutrophils, platelets, and fibrin − . 1 Abbreviations: BEL, bromoenol lactone; EDTA, ethylenediaminetetraacetic acid; EGTA, ethylene glycol tetraacetic acid; HMVEC-L, human microvascular endothelial cells-lung; iPLA 2 , calcium-independent phospholipase A 2 ; KO, knockout; PAF, platelet-activating factor; PAR-1, protease-activated receptor-1; PAR-2, protease-activated receptor-2; PLA 2 , phospholipase A 2 ; PGI 2 , prostaglandin I 2 ; WT, wild type. …”

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confidence: 99%

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Endothelial Cell Prostaglandin I₂ and Platelet-Activating Factor Production Are Markedly Attenuated in the Calcium-Independent Phospholipase A₂β Knockout Mouse

2010

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Damage and activation of lung endothelium can lead to interstitial edema, infiltration of inflammatory cells into the interstitium and airways, and production of inflammatory metabolites, all of which propagate airway inflammation in a variety of diseases. We have previously determined that stimulation of human microvascular endothelial cells from lung (HMVEC-L) results in activation of a calcium-independent phospholipase A 2 (iPLA 2 ), and this leads to arachidonic acid release and production of prostaglandin I 2 (PGI 2 ) and platelet-activating factor (PAF). We stimulated lung endothelial cells isolated from iPLA 2 β-knockout (KO) and wild type (WT) mice with thrombin and tryptase to determine the role of iPLA 2 β in endothelial cell membrane phospholipid hydrolysis. Thrombin or tryptase stimulation of WT lung endothelial cells resulted in increased arachidonic acid release and production of PGI 2 and PAF. Arachidonic acid release and PGI 2 production by stimulated iPLA 2 β-KO endothelial cells were significantly reduced compared to WT. Measured PLA 2 activity and PGI 2 production by iPLA 2 β-KO cells were suppressed by pretreatment with (R)-bromoenol lactone (R-BEL), which is a selective inhibitor of iPLA2γ. In contrast to the increase in PAF production induced by stimulation of WT endothelial cells, none was observed for KO cells, and this suggests that endothelial PAF production is entirely dependent on iPLA 2 β activity. Because inflammatory cell recruitment involves the interaction of endothelial cell PAF with PAF receptors on circulating cells, these data suggest that iPLA 2 β may be a suitable therapeutic target for the treatment of inflammatory lung diseases.Airway inflammation is involved in the pathogenesis of several acute and chronic lung diseases that include asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, emphysema, cystic fibrosis, pneumonia, and interstitial fibrosis. Exposure to injurious stimuli activates a variety of cells, including eosinophils, macrophages, mast cells, fibroblasts, smooth muscle cells, and endothelial cells, and this results in the release of vasoactive mediators, toxic metabolites, and cytokines that are involved in acute and chronic bronchoconstriction (1,2). Lung endothelial injury can result in interstitial edema which contributes to increased morbidity and mortality in pulmonary diseases (3). In addition, neutrophil infiltration facilitated by endothelial cell barrier dysfunction contributes to tissue damage in the acute phase of lung injury (4-6). † This work was supported by United States Public Health Service Grants R37-DK34388, P41-RR00954, P60-DK20579, and P30- Serine proteases such as thrombin and tryptase are released in inflammatory lung diseases. Increased numbers of mast cells are frequently observed in terminal airways, bronchoalveolar lavage fluid, and sputum of asthmatic patients (7). Allergen inhalation activates resident mast cells that release a variety of mediators, including arachidonic acid, PAF,1 histamin...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Endothelial Cell Prostaglandin I₂ and Platelet-Activating Factor Production Are Markedly Attenuated in the Calcium-Independent Phospholipase A₂β Knockout Mouse

2010

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“…On the basis of the experimental model of asthma as well as human studies it has been known that PAF administration can mimic some of the abnormalities observed in asthma, including bronchoconstriction, bronchial hyperresponsiveness, inflammatory infiltration, mucus hypersecretion, and gas exchange impairment, suggesting that PAF may contribute to the pathogenesis of bronchial asthma [41][42][43][44][45]. Similarly, increased expression of PAF receptor in eosinophils from asthmatics may be relevant to the pathogenesis of atopic asthma [10].…”

Section: The Role Of Paf In Asthmamentioning

confidence: 94%

“…PAF inhaled by normal and asthmatic subjects causes bronchoconstriction induced as the increase in non-specific bronchial reactivity [41][42][43][44][45] as well as significant disturbances in pulmonary gas exchange [53][54][55]. Following PAF inhalation, both normal and asthmatic subjects and asthmatics may however develop tachyphylaxis [41,43].…”

Section: The Role Of Paf In Asthmamentioning

confidence: 97%

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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“…PAF-AH is an enzyme that breaks down PAF and PAF-like phospholipids, which are potent mediators of inflammation. Because animal and human studies provide evidence that the administration of PAF can induce bronchoconstriction, bronchial hyperreactivity, mucus secretion, or higher vascular permeability (50)(51)(52)(53)(54)(55)(56), PAF degradation would be hypothesized to have a beneficial effect. For prevalent asthma, PAF receptor antagonists have been studied and, for the most part, have not been efficacious (15,(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67).…”

Section: Discussionmentioning

confidence: 99%

New Risk Factors for Adult-Onset Incident Asthma. A Nested Case–Control Study of Host Antioxidant Defense

Larkin

Gao

Gebretsadik³

et al. 2015

Am J Respir Crit Care Med

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Rationale: Host antioxidant defense, consisting of enzymatic antioxidant activity and nonenzymatic antioxidant micronutrients, is implicated in asthma pathogenesis. Studies of antioxidant defense and adult incident asthma have either used measures of antioxidants estimated from questionnaires or not considered enzymatic aspects of host defense.Objectives: We conducted the first study designed and powered to investigate the association of antioxidant defenses on adult incident asthma.Methods: In a nested case-control study, we followed Shanghai women (aged 40-70 years) without prevalent asthma at baseline, over 8 years. Subjects with incident asthma were ascertained prospectively by gold standard testing of symptomatic women and matched to two asymptomatic control subjects.Measurements and Main Results: Baseline urinary F2-isoprostanes, plasma concentrations of antioxidant micronutrients (tocopherols, xanthines, carotenes, and lycopene), and antioxidant enzyme activity (platelet-activating factor acetylhydrolase [PAF-AH] and superoxide dismutase) were measured from samples collected before disease onset. Among 65,372 women, 150 (0.24%) developed asthma. F 2 -isoprostane levels before asthma onset were not different between cases and control subjects. Doubling of a-tocopherol concentrations and PAF-AH activity was associated with 50 and 37% decreased risk of incident asthma (a-tocopherol: adjusted odds ratio = 0.52; 95% confidence interval, 0.32-0.84; PAF-AH: adjusted odds ratio = 0.63; 95% confidence interval, 0.42-0.93).Conclusions: In this prospective study, a-tocopherol, within normal reference ranges, and PAF-AH enzymatic activity were associated with decreased asthma development. These modifiable risk factors may be an effective strategy to test for primary asthma prevention.

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Platelet Activating Factor: Effects on Bronchomotor Tone and Bronchial Responsiveness in Human Beings

Cited by 6 publications

References 3 publications

Endothelial Cell Prostaglandin I₂ and Platelet-Activating Factor Production Are Markedly Attenuated in the Calcium-Independent Phospholipase A₂β Knockout Mouse

Endothelial Cell Prostaglandin I₂ and Platelet-Activating Factor Production Are Markedly Attenuated in the Calcium-Independent Phospholipase A₂β Knockout Mouse

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

New Risk Factors for Adult-Onset Incident Asthma. A Nested Case–Control Study of Host Antioxidant Defense

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Platelet Activating Factor: Effects on Bronchomotor Tone and Bronchial Responsiveness in Human Beings

Cited by 6 publications

References 3 publications

Endothelial Cell Prostaglandin I2 and Platelet-Activating Factor Production Are Markedly Attenuated in the Calcium-Independent Phospholipase A2β Knockout Mouse

Endothelial Cell Prostaglandin I2 and Platelet-Activating Factor Production Are Markedly Attenuated in the Calcium-Independent Phospholipase A2β Knockout Mouse

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

New Risk Factors for Adult-Onset Incident Asthma. A Nested Case–Control Study of Host Antioxidant Defense

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Product

Resources

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Endothelial Cell Prostaglandin I₂ and Platelet-Activating Factor Production Are Markedly Attenuated in the Calcium-Independent Phospholipase A₂β Knockout Mouse

Endothelial Cell Prostaglandin I₂ and Platelet-Activating Factor Production Are Markedly Attenuated in the Calcium-Independent Phospholipase A₂β Knockout Mouse