Inhaled budesonide fails to inhibit the PAF‐induced increase in plasma leukotriene B4 in man.

Abstract

1 We studied the ability of inhaled budesonide to modulate PAF-induced acute effects in nine healthy nonsmoking volunteers. Responses in inflammatory cells and mediators in peripheral blood as well as in pulmonary function and circulation were monitored.2 Inhalation of increasing doses of PAF (total cumulative dose of 500 Pg) caused a rapid and profound decrease in circulating white blood cells, especially in granulocytes (P < 0.01), which was turned to an increased number of these cells (P < 0.05, P < 0.025, respectively) in the blood samples taken 8 min after completion of the PAF challenge.No changes in the circulating platelets or their thromboxane production were found. Plasma concentrations of histamine or methylhistamine remained unchanged during PAF-inhalation, while plasma LTB4 tripled from the baseline level at 10 min (P < 0.0005) and was returned to the pre-PAF value at 60 min. 3 PAF inhalation induced a bronchial obstruction (P < 0.025), but no bronchial hyperresponsiveness to methacholine was found in any of our subjects when measured 24 h after the PAF challenge. Furthermore, PAF caused a decrease in systolic blood pressure (P < 0.05). 4 Budesonide pretreatment of 400 ,ug twice daily during the preceding 5 days had no effect on any PAF-induced events measured in our study. That fact may also contradict the role of bronchial resident or alveolar cells as a source of the PAFinduced LTB4 burst in plasma. 5 We conclude that in healthy volunteers inhaled PAF induces a marked increase in plasma LTB4, which is not inhibited by inhaled budesonide. We suggest that LTB4 originates from the circulating neutrophils activated in the bronchial capillary net by inhaled PAF. The failing plasma histamine response during PAF provocation contradicts a main role of this mediator in PAF-induced bronchial obstruction or circulatory events.

Pathological Aspects of Platelet-Activating Factor (PAF)

“…The effects of PAF in hyperactivity, however, were bimodal (NIEMINEN ct al. 1994) and not easily reproducible in normal man (Hopp et al 1989;LAI et al 1990;STENTON et al 1990;SPENCER et al 1990SPENCER et al ,1991NIEMINEN et al 1991bNIEMINEN et al , 1992 as well as less pronounced than those of antigen (MARSH et al 1985) or C 5a (IRVIN et al 1986). IV injections of PAF into guinea pigs also induce typical signs and disturbances that go with extravascular platelet recruitment (LELLOUCH-TUBIANA et al 1985).…”

“…IV injections of PAF into guinea pigs also induce typical signs and disturbances that go with extravascular platelet recruitment (LELLOUCH-TUBIANA et al 1985). Furthermore, bronchial spasms by PAF were observed in humans (GATEAU et al 1984;Cuss et al 1986;NIEMINEN et al 1991bNIEMINEN et al , 1992. The bronchospasms by PAF in guinea pigs are reduced by capsaicin (SPINA et al 1991), indicating the involvement of neuropeptides (PERRETTI and MANZINI 1992), and by lipoxygenase inhibitors and the slowreacting-substance (SRS) antagonist FPL-5572 (BONNETT et al 1983), indicating that leukotrienes are secondary mediators of histamine release (HALON EN et al 1985).…”