Enhanced production of platelet activating factor by peripheral granulocytes from children with asthma

Abstract

Granulocytes from 23 asthmatic children aged 4-15 years and 32 age-matched healthy children were studied. Cells were purified by Dextran sedimentation and Percoll gradient centrifugation from heparinized blood. After in vitro stimulation by ionophore A23187 the amount of newly synthesized PAF and LTC4 was assessed by radio receptor assay or radioimmunoassay respectively. Eight patients had symptoms of asthma within the last 3 weeks before examination. Granulocytes from the symptomatic patients showed a significantly higher PAF generation (median 125 ng/10(6) cells, range 7-189 ng/10(6) cells) when compared to asymptomatic patients (p less than 0.001, median 14 ng/10(6) cells, range 6-33 ng/10(6) cells) or controls (p less than 0.001, median 11 ng/10(6) cells, range 3-26 ng/10(6) cells). In contrast, LTC4 generation was increased in both patient groups. The results suggest a regulatory role of PAF in the exacerbation of asthma.

Platelet-activating factor exerts mitogenic activity and stimulates expression of interleukin 6 and interleukin 8 in human lung fibroblasts via binding to its functional receptor.

“…Inhalation of PAF provokes asthma-like airway responses such as bronchoconstriction, bronchial hyperresponsiveness (1-3), increased vascular permeability (4,5), and mucosal edema (4,5). Recently, it has been shown that circulating PAF is markedly increased during acute asthmatic attacks (3,6,7).…”

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

“…While PAF may not be the primary effector in the asthmatic response, it may act as a priming agent in a network of lipid mediators and cytokines involved in the chronic inflammatory process [5,19], and there is also evidence that systemic PAF concentrations are increased during acute asthma. A23187-stimulated granulocyte PAF production and plasma PAF levels are reported to be higher in children with asthma symptoms compared with asymptomatic or control children [16,17], and in patients with mild asthma, blood PAF levels were increased following allergen-induced bronchoconstriction [15] and during spontaneous exacerbations [18].…”

“…However, PAF has been detected in bronchoalveolar lavage fluid (BAL) from asthmatics [13], and allergen challenge has resulted in high levels of lyso-PAF in nasal fluids [14], and increased plasma PAF concentrations [15]. A number of recent studies have also suggested that systemic PAF concentrations may be increased in symptomatic asthmatic subjects [16][17][18]. Despite these observations, the interpretation of such measurements is complicated by factors such as the short half-life of PAF, the fact that lyso-PAF is both a precursor and metabolite of PAF, the likelihood that PAF acts mainly at localized sites of inflammation and that it may be rapidly metabolized and reincorporated by surrounding inflammatory cells [19].…”

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

“…The fact that it also induces endothelial cell alteration with expression of adhesion mol ecules (ICAM-1) [27,28] and causes the generation and re lease of cyclo-oxygenase products in eosinophils [23] may provide potential mechanisms for the transient platelet pooling and activation in the lung reported in asthma bronchiale [8,22]. Direct determination of PAF concentrations have been performed in several studies [7,25,26,29] with conflicting results. The values o f the plasma concentrations in healthy donors vary between undetectable [25] and 2.5x10 8 A / [7] and data from patients with allergic rhinitis, cold urticaria and asthma bronchiale indicate a broad range between 10 12 M [25] and 10 M [7], However, the latter con centration appears less likely to occur in vivo because one would expect systemic platelet aggregation and severe thrombocytopenia.…”

“…We cannot rule out a contri bution of other mediators to the decreased response, but its apparent selectivity for PAF (and not for other agonists) makes this mechanism less likely. Since platelets possess 1,100 receptors for PAF with a K(1 o f 0.074 nM [29] it appears likely that the concentration reported could lead to sub threshold platelet activation and desensitization. Locally higher concentrations may lead to the previously reported platelet pooling in the lung and may explain the observed release reaction of BTG and PAF [8], perhaps in combina tion with other platelet agonists; platelet aggregates ob structing the capillary network of the lung may further ag gravate the hypoxemia in these patients.…”