Allergen Exposure in Acute Asthma Causes the Release of Platelet-Activating Factor (PAF) as Demonstrated by the Desensitization of Platelets to PAF

Beer, Jürg H.; Wüthrich, B; Felten, A von

doi:10.1159/000236857

Cited by 21 publications

(17 citation statements)

References 13 publications

(22 reference statements)

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“…Increased levels of PAF also have been reported in children with acute asthmatic attacks (10). The desensitized state of human platelets has been used as an index of previous exposure to PAF and was shown to correlate with responsiveness to inhalation of specific allergens (11). Transgenic mice expressing the PAF receptor are more susceptible to methacholine-induced bronchial hypersensitivity than normal littermates (12), and a significant increase in PAF receptor mRNA levels has been reported in the lungs of asthmatic patients (13).…”

Section: Introductionmentioning

confidence: 99%

Deficiency of platelet-activating factor acetylhydrolase is a severity factor for asthma

Stafforini¹,

Numao²,

Tsodikov³

et al. 1999

J. Clin. Invest.

119

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Asthma, a family of airway disorders characterized by airway inflammation, has an increasing incidence worldwide. Platelet-activating factor (PAF) may play a role in the pathophysiology of asthma. Its proinflammatory actions are antagonized by PAF acetylhydrolase. A missense mutation (V279F) in the PAF acetylhydrolase gene results in the complete loss of activity, which occurs in 4% of the Japanese population. We asked if PAF acetylhydrolase deficiency correlates with the incidence and severity of asthma in Japan. We found that the prevalence of PAF acetylhydrolase deficiency is higher in Japanese asthmatics than healthy subjects and that the severity of this syndrome is highest in homozygous-deficient subjects. We conclude that the PAF acetylhydrolase gene is a modulating locus for the severity of asthma. J. Clin. Invest. 103:989-997

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Section: Introductionmentioning

confidence: 99%

Deficiency of platelet-activating factor acetylhydrolase is a severity factor for asthma

Stafforini¹,

Numao²,

Tsodikov³

et al. 1999

J. Clin. Invest.

119

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“…Aller gen exposure of asthmatics induces the release of PAF as demonstrated by platelet desensitization [12].…”

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confidence: 99%

Specific High Affinity Binding of Platelet Activating Factor to Intact Human Blood Neutrophils and Eosinophils

Korth

1996

Int Arch Allergy Immunol

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Neutrophils and eosinophils are involved in various inflammatory reactions such as leukocyte migration, adherence and phagocytosis. A regulation of platelet-activating factor (PAF) receptors in intact human blood neutrophils and eosinophils is clinically important. Intact human blood neutrophils and eosinophils prepared under sterile conditions specifically bound [³H]PAF in the presence of fatty acid-free serum albumin (0.25% BSA). Excess unlabeled PAF (500 nM) or the specific PAF receptor antagonist WEB 2086 (1 μM) inhibited the [³H]PAF binding. PAF receptors on the surface of intact blood neutrophils and eosinophils had high affinity K_d values of 0.55 and 2.3 vM at 4°C. The B_max values were 200 fmol/2.5 × 10⁶ neutrophils and 26 fmol/2.5 × 10⁵ eosinophils. PAF receptors on the outer plasma membranes were functionally relevant as high dose PAF displaced WEB 2086 after 3 min preincubation mediating maximal cytosolic [Ca²⁺]i flux. High doses of PAF or phorbol myristate acetate (PMA) downregulated neutrophils and a low dose PAF decreased the specific [³H]PAF binding to eosinophils determined with WEB 2086 at 20°C. Only neutrophils were significantly upregulated by low dose PAF (5 nM), lyso PAF or low dose PMA (1 nM). Up- and downregulation by PAF itself of neutrophil and eosinophil PAF receptors might explain their desensitization and some clinical controversy concerning the role of PAF in inflammatory and allergic diseases. The latter hypothesis would lead to a novel combination of antagonists against PAF receptors and PAF production.

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“…It is also possible that PAF released systemically during acute asthma may itself feedback to modify neutrophil acetyltransferase with a resultant lowering of the Km. An analogous desensitisation of platelets to in vitro stimulation by PAF has been observed following allergen inhalation by asthmatic patients, which presumably causes systemic PAF release in vivo [29].…”

Section: Discussionmentioning

confidence: 55%

Lyso-PAF acetyltransferase activity in neutrophils of patients during acute asthma and after recovery

Misso

Gillon²,

Stewart³

et al. 1996

Eur Respir J

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L Ly ys so o--P PA AF F a ac ce et ty yl lt tr ra an ns sf fe er ra as se e a ac ct ti iv vi it ty y i in n n ne eu ut tr ro op ph hi il ls s o of f p pa at ti ie en nt ts s d du ur ri in ng g a ac cu ut te e a as st th hm ma a a an nd d a af ft te er r r re ec co ov ve er ry y ABSTRACT: The production of platelet-activating factor (PAF) by inflammatory cells is regulated by lyso-PAF acetyltransferase, and the activity of this enzyme is increased in neutrophils of stable asthmatic patients. The aim of this investigation was to determine whether acetyltransferase activity is further upregulated in asthmatic patients experiencing acute symptoms. A radioenzymatic assay was used to measure the enzymatic affinity constant (Km) and maximal enzymatic activity (Vmax) for acetyltransferase from unstimulated and Ca 2+ ionophore (A23187)-stimulated neutrophils from 16 patients with acute asthma, and the measurement was repeated at the time of discharge (n=9) and after recovery from the acute episode (n=13).During acute asthma, Km (median 93.8 (interquartile range 64.1-109.7) µM) was lower than that measured in nonasthmatic subjects in a previous study using identical methods (155.1 (122.2-179.9) µM; p=0.0001), and in 10 out of 13 acute patients Km for unstimulated neutrophils increased following recovery. In A23187-stimulated neutrophils, Km during acute asthma (84.3 (73.6-100.2) µM) and at discharge (83.9 (83.1-94.8) µM) were similar, but Km after recovery was increased (115.0 (95.6-119.5) µM; p=0.02). The change in Km following stimulation with A23187 was also significantly less during acute asthma than previously measured in nonasthmatic subjects (p=0.003). Although Vmax during acute asthma (12.9 (interquartile range 10.5-22.5) nmol·min -1 ·mg -1 protein) did not differ significantly from that at discharge (14.4 (12.3-20.4) nmol·min -1 ·mg -1 ) or after recovery (17.3 (12.3-18.4) nmol·min -1 ·mg -1 ), both median Km and Vmax tended to be lowest during acute asthma and increase at discharge and after recovery.An increase in lyso-PAF acetyltransferase activity alone may not account for increased systemic PAF concentrations during acute asthma. However, the reduction in the enzymatic affinity constant and its smaller change following in vitro stimulation suggest that alterations in the affinity of acetyltransferase for acetylcoenzyme A (CoA) and in the regulation of enzyme activity may be occurring during acute asthma.

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Allergen Exposure in Acute Asthma Causes the Release of Platelet-Activating Factor (PAF) as Demonstrated by the Desensitization of Platelets to PAF

Cited by 21 publications

References 13 publications

Deficiency of platelet-activating factor acetylhydrolase is a severity factor for asthma

Deficiency of platelet-activating factor acetylhydrolase is a severity factor for asthma

Specific High Affinity Binding of Platelet Activating Factor to Intact Human Blood Neutrophils and Eosinophils

Lyso-PAF acetyltransferase activity in neutrophils of patients during acute asthma and after recovery

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