Inhaled PAF stimulates leukotriene and thromboxane A2 production in humans

Abstract

Platelet-activating factor (PAF) is a potent bronchoconstrictor in humans and has been implicated as an inflammatory mediator in asthma. This study was performed to evaluate whether PAF-induced bronchoconstriction in vivo could be mediated through the release of the bronchoconstrictor eicosanoids, thromboxane (Tx) A2 and the cysteinyl leukotrienes. Ten asthmatic subjects were studied on three occasions after bronchial challenges with aerosolized PAF, methacholine, or isotonic saline. PAF caused bronchoconstriction in all 10 subjects (mean maximal percent fall in specific airway conductance 48.2 +/- 4.6) and was matched by methacholine challenge. Saline caused no changes in specific airway conductance. Urinary leukotriene E4 was significantly elevated after inhaled PAF (366.0 +/- 66.9 ng/mmol creatinine, P less than 0.01) compared with methacholine (41.6 +/- 13.3) and saline (33.6 +/- 4.6). The major urinary TxA2 metabolite 2,3-dinor TxB2 was elevated after inhaled PAF (41.3 +/- 7.1 ng/mmol creatinine, P less than 0.01) compared with methacholine (14.0 +/- 2.7) and saline (17.1 +/- 3.9). Urinary 2,3-dinor 6-oxo-prostaglandin F1 alpha after PAF (22.2 +/- 1.4) was raised with respect to the methacholine challenge (13.9 +/- 1.8, P less than 0.02), although no significant increase was observed compared with the saline control (18.6 +/- 3.3). Inhaled PAF leads to the secondary generation of cysteinyl leukotrienes and TxA2, and it is possible that these mediate some of the acute effects of inhaled PAF in vivo.

Role of platelet-activating factor in pneumolysin-induced acute lung injury

“…In humans, increased PAF levels have been found in pneumonia (46), acute respiratory distress syndrome (47), and sepsis (48,49). However, there is only limited information on signaling pathways responsible for the responses to PAF in human tissue: PAF inhalation stimulated leukotriene and TXA 2 production in humans (50), and PAF activated PKC in human umbilical cord vein endothelial cells (51) and human epidermoid carcinoma cells (52) and activated Rho family proteins in human monocytic leukemia cells (53). These studies denote that a potential involvement of PAF in human pneumococcal pneumonia may include similar mechanisms as shown in our murine study.…”

Nasal eosinophilia induced by PAF-acether is accompanied by the release of eosinophil cationic protein

“…Moreover, increased urinary levels of peptide leukotrienes and thromboxane A 2 have been found by TAYLOR et al [9] in subjects undergoing bronchial stimulation with PAF. Therefore, an increase in iLTC 4 levels in nasal lavage fluids could be expected, but we have not found any significant iLTC 4 release.…”

“…Furthermore, nasal neutrophilia and eosinophilia have been observed after challenge with PAF, with a more rapid and more marked response in atopic than in normal subjects [6]. PAF is recognized as a potent bronchoconstrictor in humans [7], but some of its effects in vivo may be mediated indirectly by the release of secondary mediators [8][9][10][11]. Cyclo-oxygenase inhibitors and thromboxane or leukotriene (LT) antagonists can modulate PAF-induced bronchoconstriction, suggesting that these substances could mediate some PAF-induced effects on respiratory airways [8,10,11].…”

Acute bronchial obstruction following inhalation of PAF in asthmatic and normal subjects: comparison with methacholine

“…The explanation for the tachyphylaxis seen after inhalation of PAF is not clear but could be due to a rapid internalization of the PAF receptors on the surface of the resident cells, possibly involved in the release of secondary bronchoconstricting mediators. Several studies performed both in vitro and in vivo suggest that leukotrienes may be involved [19][20][21][22]. An alternative explanation for the tachyphylaxis might be the fact that the first dose of PAF causes a plasmatic exudation in the bronchial mucosa [23], causing a rapid metabolization by acetyl-hydrolase [1] of any further dose of PAF locally delivered.…”