Platelet-activating Factor Inhalation Research Articles

The effect of lipoprotein-associated phospholipase A2 deficiency on pulmonary allergic responses in aspergillus fumigatus sensitized mice

BackgroundLipoprotein-associated phospholipase A2 (Lp-PLA2)/platelet-activating factor acetylhydrolase (PAF-AH) has been implicated in the pathogenesis of cardiovascular disease. A therapeutic targeting of this enzyme was challenged by the concern that increased circulating platelet activating factor (PAF) may predispose to or increase the severity of the allergic airway response. The aim of this study was to investigate whether Lp-PLA2 gene deficiency increases the risk of PAF and IgE-mediated inflammatory responses in vitro and in vivo using mouse models.MethodsLp-PLA2-/- mice were generated and back crossed to the C57BL/6 background. PAF-AH activity was measured using a hydrolysis assay in serum and bronchoalveolar lavage (BAL) samples obtained from mice. Aspergillus fumigatus (Af)-specific serum was prepared for passive allergic sensitization of mice in vivo and mast cells in vitro. β- hexosaminidase release was studied in bone marrow derived mast cells sensitized with Af-specific serum or DNP-IgE and challenged with Af or DNP, respectively. Mice were treated with lipopolysaccharide (LPS) and PAF intratracheally and studied 24 hours later. Mice were sensitized either passively or actively against Af and were studied 48 hours after a single intranasal Af challenge. Airway responsiveness to methacholine, inflammatory cell influx in the lung tissue and BAL, immunoglobulin (ELISA) and cytokine (Luminex) profiles were compared between the wild type (WT) and Lp-PLA2-/- mice.ResultsPAF-AH activity was reduced but not completely abolished in Lp-PLA2-/- serum or by in vitro treatment of serum samples with a high saturating concentration of the selective Lp-PLA2 inhibitor, SB-435495. PAF inhalation significantly enhanced airway inflammation of LPS treated WT and Lp-PLA2-/- mice to a similar extent. Sensitized WT and Lp-PLA2-/- bone-marrow derived mast cells released β-hexosaminidase following stimulation by allergen or IgE crosslinking to equivalent levels. Wild type and Lp-PLA2-/- mice responded to passive or active allergic sensitization by significant IgE production, airway inflammation and hyperresponsiveness after Af challenge. BAL cell influx was not different between these strains while IL-4, IL-5, IL-6 and eotaxin release was attenuated in Lp-PLA2-/- mice. There were no differences in the amount of total IgE levels in the Af sensitized WT and Lp-PLA2-/- mice.ConclusionsWe conclude that Lp-PLA2 deficiency in C57BL/6 mice did not result in a heightened airway inflammation or hyperresponsiveness after PAF/LPS treatment or passive or active allergic sensitization and challenge.

Effects of NZ-107 on airway inflammation and cell activation in guinea-pigs.

The effects of NZ-107 on some airway inflammation models and the generation of superoxide anion (O2-) were studied in guinea-pigs. Airway inflammation was caused by intra-tracheal injection of murine recombinant interleukin-5 (mrIL-5, 15 micrograms/animal), inhalation of platelet-activating factor (PAF, 0.003%) and intra-tracheal injection of leukotriene B4 (LTB4, 10 micrograms/animal). NZ-107 (4-bromo-5-(3-ethoxy-4-methoxybenzylamino)-3(2H)-pyridazinone) at a dose of 50 mg kg-1, intraperitoneally reduced mrIL-5- and PAF-induced eosinophilia. This compound at a dose of 25 and 50 mg kg-1 also suppressed LTB4-induced eosinophilia and neutrophilia in bronchoalveolar lavage fluid (BALF). On the other hand, prednisolone at a dose of 20 mg kg-1, i.p., prevented the increased number of macrophages, eosinophils and neutrophils induced by mrIL-5, the increased number of eosinophils induced by PAF and the increased number of eosinophils and neutrophils induced by LTB4 in BALF. Furthermore, both drugs reduced mrIL-5- or PAF-induced increase in the number of airway epithelial cells in BALF. The generation of O2- was measured by the method of cytochrome C reduction. NZ-107 (10-100 micrograms mL-1) attenuated PAF- and FMLP-induced O2- production from macrophages and reduced PAF-induced O2- generation by eosinophils but had no effect on that from neutrophils. These results indicate that NZ-107 prevents the increased number of pulmonary eosinophils and airway epithelial cells and the activation of macrophages and eosinophils, suggesting that NZ-107 may be useful as a remedy for airway inflammatory diseases such as bronchial asthma.

Roxythromycin Reinforces Epithelial Defence Function in Rabbit Trachea

Our study elucidates the effect of roxythromycin (RXM) on airway epithelial defence functions, especially the mucociliary and epithelial barrier functions, in the rabbit trachea. In vitro ciliary activity was not affected in the presence of 3.3 mg/ml of RMX, but was enhanced in the presence of 6.7 mg/ml of RXM. Oral administration of 10 and 100 mg of RXM for 14 days enhanced both ciliary activity and mucociliary transport velocity in the trachea. Epithelial permeability to fluorescein isothiocyanate-dextrans (FD-70s; molecular weight: 70,000 daltons) was not affected by oral administration of 10 mg of RXM for 14 days, but was significantly reduced by oral administration of 100 mg of RXM for 14 days. Inhalation of platelet activating factor (PAF) compromised the function of the mucociliary system and the tight junction barrier. However, pretreatment with 20 mg of RXM significantly alleviated the PAF-induced decrease in mucociliary function and the increase in epithelial permeability to FD-70s. In conclusion, such reinforcement of the epithelial defence functions is likely to be involved in the pharmacological action underlying the clinical efficacy of RXM for chronic airway inflammatory disease.

A risk-benefit assessment of natural and synthetic exogenous surfactants in the management of neonatal respiratory distress syndrome.

Alveolar surfactant is central to pulmonary physiology. Quantitative and qualitative surfactant abnormalities appear to be the primary aetiological factors in neonatal respiratory distress syndrome (RDS) and exogenous replacement of surfactant is a rational treatment. Available exogenous surfactants have a natural (mammal-derived lung surfactants) or synthetic origin. Pharmacodynamic and clinical studies have demonstrated that exogenous surfactants immediately improve pulmonary distensibility and gas exchange; however, this is achieved more slowly and with more failures with synthetic surfactants. The ensuing advantageous haemodynamic effects are not so striking and they include an inconvenient increased left to right ductal shunt. Two strategies of administration have been used: prophylactic or rescue therapy to treat declared RDS. All methods of instillation require intubation. In addition to the early benefits (improved gas exchange and reduced ventilatory support) the incidence of classical complications of RDS, especially air leak events, is decreased except for the uncommon problem of pulmonary haemorrhage. The incidence of bronchopulmonary dysplasia is neither uniformly nor significantly reduced although the severity appears to be lessened. The overall incidence of peri-intraventricular haemorrhages is not diminished although separate trials have shown a decreased rate. The most striking beneficial effect of exogenous surfactants is the increased survival (of about 40%) of treated very low birthweight neonates. A small number of adverse effects has been described. The long term outcome of survivor neonates with RDS treated with surfactants versus control neonates with RDS not treated with surfactants is similar in terms of physical growth, at least as good in terms of respiratory status, with a similar or slightly better neurodevelopmental outcome. There is not clear benefit of exogenous surfactant therapy in extremely premature infants (< 26 weeks gestational age, birthweight < 750 g). The potential risks of contamination, inflammatory and immunogenic reaction and the inhalation of platelet activating factor remain a theoretical concern of surfactant therapy which has not been confirmed in clinical practice. The optimal timing of treatment favours prophylaxis over rescue treatment and early rescue treatment rather than delayed therapy. Meta-analyses suggest the clinical superiority of natural surfactant extracts over a synthetic one (colfosceril palmitate). The economic impact of surfactant therapy is favourable and the costs per quality-adjusted life year (QALY) for surviving surfactant treated infants are low. In conclusion, the mid and long term benefit/risk ratio clearly favours the use of exogenous surfactants to prevent or to treat RDS in neonates who have a gestational age of > 26 weeks or a birthweight of > 750 g, especially with the prophylactic strategy using natural surfactant extracts.

Platelet activating factor compromises airway epithelial defense functions

Background: The mechanism of disruption of the epithelial defense function observed in asthmatic airways is considered to be largely the result of mediators involved in allergic responses. Platelet activating factor (PAF) might be a key mediator involved in this mechanism. Objective: This study was designed to determine whether PAF is capable of compromising the epithelial defense functions, such as tight junctional barriers and the mucociliary system. Methods: A total of 120 healthy rabbits were used. Twenty of them were used as normal controls. Eighty rabbits were treated with inhalation of 10 ml of PAF (200 μg/ml), and 20 animals were used for the examination of epithelial defense functions of the trachea at 1, 10, 20, and 30 days after inhalation of PAF. Epithelial defense functions of the trachea were evaluated by ciliary activity, mucociliary transport velocity, epithelial permeability to fluorescein isothiocyanate dextrans (70,000 d), and electron microscopy of the epithelial structure. Results: PAF inhalation induced a significant decrease in ciliary activity and mucociliary transport velocity, which persisted for up to 20 days. PAF inhalation also caused a significant 7.4-fold increase in epithelial permeability to fluorescein isothiocyanate dextrans at 1 and 10 days. This increased epithelial permeability returned to the normal level 20 days after PAF inhalation. However, electron microscopy demonstrated no apparent evidence of epithelial shedding. Conclusions: PAF-induced prolonged dysfunction of both the epithelial junctional barrier and the mucociliary system may allow enhanced entry of allergen molecules, as well as bronchoactive agonists to the airway parenchyma and may also significantly contribute to an increased airway responsiveness. (J Allergy Clin Immunol 1997;100:520-6.)

The effect of inhalation of platelet-activating factor on the pulmonary clearance of 99mTc-DTPA aerosol.

Platelet-activating factor (PAF) is a short-acting, lipid-soluble autocoid, inhalation of which causes an immediate pulmonary vascular sequestration of granulocytes and a peripheral neutropenia. We investigated the effect of PAF inhalation on the pulmonary clearance rate of inhaled 99mTc-DTPA in order to test the hypothesis that the pulmonary sequestration of granulocytes results in acute lung injury. In nine normal nonsmoking adults, the rate of clearance of DTPA, corrected for background activity, was 1.5 (SD 0.7) %/min over the first 10 min after inhalation. Inhalation of 4.8 micrograms PAF abruptly increased the clearance rate to a mean value of 2.3 (1.4) %/min (p < 0.05). No increase in clearance was observed in four nonsmoking subjects who inhaled vehicle only. The mean overall increase after PAF was 87% of the baseline clearance, significantly different (p < 0.05) from the corresponding change in the control group, which was -17%. After PAF, the clearance rate returned to baseline values within 10 min in all subjects. In all subjects who inhaled PAF, but in none who inhaled vehicle, there was an immediate neutropenia of 51 (SD 25) % of the baseline value (p < 0.01). This neutropenia persisted longer than the corresponding accelerated DTPA clearance and was still 74 (36) % of the baseline value at 10 min. Furthermore, there was no correlation between the increase in DTPA clearance induced by PAF inhalation and the decrease in peripheral blood granulocyte count. We conclude that PAF inhalation results in an increase in pulmonary DTPA clearance, probably not mediated by pulmonary vascular granulocyte sequestration.

Changes in bronchial responsiveness, circulating leucocytes and ex vivo cytokine production by blood monocytes after PAF inhalation in allergic asthmatics

We investigated the effects of inhaled platelet-activating factor (PAF) on methacholine bronchial responsiveness, circulating leucocyte counts, and ex vivo tumour necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1) production from blood monocytes in eight allergic asthmatics. Bronchial responsiveness was defined as the provocative concentration of methacholine causing a 20% decrease in forced expiratory volume in one second (PC20). Circulating leucocytes were counted by means of an automatic haemocytometer, and cytokines were measured with specific immunoassays. The different variables were measured before and 4, 24, 48, 72 and 168 h after a PAF (225 micrograms), a lyso-PAF (225 micrograms) and a saline bronchial challenge. When compared with lyso-PAF and saline, inhalation of PAF resulted in a significant decrease in PC20 over a period of one week. Two falls in bronchial responsiveness were identified, the first by 4 h and the second beginning 48 h and reaching a maximum by 168 h. The increases in spontaneous TNF alpha and IL-1 production which occurred during the week after both PAF, lyso-PAF and saline, did not differ significantly. Likewise, the changes in circulating neutrophil counts, characterized by a transient rise by 4 h after PAF and lyso-PAF but not saline, followed by a fall by 24 h and a persistent decrease until 168 h, were not significantly different after PAF, lyso-PAF and saline. On the other hand, in comparison with lyso-PAF and saline, inhaled PAF caused a significant protracted augmentation in circulating eosinophil counts, which was maximal by 48 h but did not correlate with the delayed decline in PC20.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Bronchial and Hematologic Effects Following Inhalation of a Single Dose of PAF

This study compared the acute bronchial and hematologic effects of inhaled platelet activating factor (PAF) (30 micrograms as a single dose) in 19 patients with mild asthma and 19 normal subjects. Each subject underwent a methacholine bronchial challenge 1 week before PAF challenge to determine the concentration of methacholine causing a 20 percent fall in FEV1 (PC20M). On the day of PAF challenge, specific conductance (SGaw), FEV1, FEF25-75, and platelet and leukocyte counts were measured before, and 5, 10, 15, and 20 min after PAF inhalation. Changes in pulmonary and hematologic parameters were expressed as percent of control (saline solution/ethanol solution). Unlike normal subjects, subjects with asthma had bronchial hyperresponsiveness to methacholine: geometric mean (range): 0.59 mg/ml (0.07 to 9.8) vs > 32 mg/ml. Acute bronchial obstruction over the first 20 min after PAF inhalation was more pronounced in asthmatics than in normal subjects whatever the functional index considered (p < 0.01). In asthmatics (n = 19), mean (SEM) maximal fall in SGaw, FEV1, and FEF25-75 reached 50 percent (6), 11 percent (4), and 19 percent (5), respectively, while in normal subjects (n = 19) the maximal decreases were 24 percent (6), 4 percent (1), and 6 percent (1), respectively. In asthmatics, no correlation was found between log PC20M and log fall in FEV1 after PAF (r = 0.04 p > 0.05). In asthmatics and normal subjects, inhaled PAF caused a transient fall in neutrophils and monocytes by 5 min followed by a full recovery at 15 min and 20 min. These hematologic changes were not significantly different between the two groups. While not correlated with their airway responsiveness to methacholine, asthmatics, compared with normal subjects, develop an exaggerated acute airway obstruction in response to PAF. In contrast, hematologic changes induced by PAF do not differ between asthmatics and normal subjects.

Inhibitory effect of UK,74505, a potent and specific oral platelet activating factor (PAF) receptor antagonist, on airway and systemic responses to inhaled PAF in humans.

Inhaled PAF provokes bronchoconstriction, causes peripheral blood neutropenia with rebound neutrophilia, and generates urinary production of the bronchoconstrictor eicosanoids, thromboxane (TX)A2, and the cysteinyl leukotrienes. We examined the effects of an oral PAF antagonist UK,74505 on each of these responses to a single 36 micrograms dose of inhaled PAF. In a double-blind randomized placebo-controlled crossover study, 12 normal male subjects inhaled PAF on two consecutive days, 3 and 24 h after intake of two doses of UK,74505 25 mg and 100 mg, or matched placebo (P). After P, inhalation of PAF provoked bronchoconstriction, measured at regular time points for 60 min as a change in sGaw from baseline and computed as area under the curve (AUC), induced a neutropenia at 5 min and rebound neutrophilia at 2 h, and stimulated production of urinary eicosanoids. Bronchoconstriction was maximal at 5 min but had receded at 1 h; (AUC mean [95% Cl]; 20.0 [13.2, 26.8] at 3 h; 11.0 [5.3, 16.6] at 24 h) and was completely abolished by both doses of UK,74505 at 3 h and by the higher 100 mg dose at 24 h. PAF-induced neutropenia and rebound neutrophilia were abolished by both doses of drug; neutropenia at 5 min (expressed as mean [95% Cl] change from baseline; -2.5 x 10(9)/L [-2.9, -2.1] after P; -0.3 [-0.7, 0.1] after 25 mg; 0.1 [-0.3, 0.4] after 100 mg), neutrophilia at 2 h (2.0 [-1.3, 2.6] after P; -0.2 [-0.8, 0.5] after 25 mg; -0.1 [-0.8, 0.5] after 100 mg).(ABSTRACT TRUNCATED AT 250 WORDS)

No Increase in Plasma Histamine During PAF-induced Airway Obstruction in Allergic Asthmatics

To investigate the possible role of mast cell or basophil histamine release in mediating platelet-activating factor (PAF) airway obstruction, we studied the effect of inhaled PAF (30 micrograms, single dose) on plasma histamine, bronchial caliber, and leukocyte and platelet counts in six patients with mild or moderate allergic asthma (mean age, 27 +/- 1.3 years; mean FEV1, 95 +/- 5 percent of predicted; mean PC20 methacholine, 1.46 +/- 0.36 mg/ml). Specific conductance (SGaw) FEV1, FEF25-75 percent, differential leukocyte and platelet counts, and plasma histamine (radioimmunoassay) were measured before and 5, 10, 15, and 20 min after PAF inhalation. Mean basal plasma histamine level was 0.28 +/- 0.04 ng/ml. Inhalation of PAF caused a fall in SGaw peaking at 5 min (43 +/- 9 percent) and a fall in FEV1 and FEF25-75 peaking at 10 min (19 +/- 10 percent and 30 +/- 13 percent, respectively). There was also a rapid and transient fall in circulating neutrophils at 5 min (from 3,096 +/- 204/mm3 to 2,551 +/- 158/mm3, p < 0.05) followed by a rebound neutrophilia. In contrast, plasma histamine level did not change significantly at any time measured. Conversely in the same asthmatics, a rapid rise in plasma histamine level (from 0.29 +/- 0.03 ng/ml at baseline to 0.53 +/- 0.06 ng/ml at 5 min; p < 0.01) was observed after an allergenic challenge (Dermatophagoides pteronyssinus) causing a fall in FEV1 peaking at 10 min (22 +/- 4 percent). Thus, inhaled PAF may induce airway obstruction and neutropenia in asthmatics without any significant change of plasma histamine level. These results indicate that it is unlikely that lung mast cells or basophils degranulate during PAF-induced bronchoconstriction.

Platelet-activating factor does not induce bronchial hyperreactivity in nonasthmatic subjects.

Platelet-activating factor (PAF) is a phospholipid which plays a role as a mediator in inflammation. Recently, it has been implicated in the induction of bronchial hyperresponsiveness in man. In order to establish the effect of PAF on bronchial reactivity, 6 normal subjects without bronchial hyperresponsiveness inhaled 400 micrograms of PAF in 10 divided cumulative doses. All subjects felt a hot flush and a slight tracheal irritation after the inhalation of PAF. Forced expiratory flows (FEF) were measured between each inhalation of PAF and did not change significantly. Bronchial reactivity to methacholine (MCH up to a dose of 2 mg) was determined 1, 7, 14 and 21 days after inhalation of PAF. Forced expiratory volume in 1 s (FEV1), forced expiratory flow between 25 and 75%, and at 75% of vital capacity (FEF25-75% and FEF75%) measured after the inhalation of 2 mg of MCH did not differ significantly from baseline values determined before PAF challenge. In conclusion, the administration of PAF by inhalation in tolerable doses does not induce bronchial hyperresponsiveness as determined by a reduction of 20% of FEV1 nor by more sensitive indicators of ventilatory obstruction, such as FEF25-75% and FEF75%.

Effects of single and multiple inhalations of platelet-activating factor on airway cell composition and responsiveness in monkeys.

Platelet-activating factor (PAF) is a potent pro-inflammatory mediator that may play a role in the pathogenesis of airway hyper-responsiveness and asthma. In man, a single inhalation of PAF induces a small but prolonged increase in airway responsiveness in some individuals. The purpose of this study was to determine the effects of single and multiple inhalations of PAF on airway cell composition and responsiveness in monkeys. Anaesthetized and intubated adult male cynomolgus monkeys were studied. Airway cell composition was measured by bronchoalveolar lavage (BAL). Airway responsiveness was measured by determining the concentration (PC100) of inhaled methacholine that caused a 100% increase in respiratory system resistance (Rrs). Airway cell composition (BAL) and responsiveness (PC100) were determined 1 day before and 20 hr after a single inhalation of PAF (approximately 200 micrograms) or 3 days before (Day 0) and 3 days after (Day 10) 3-alternate-day (Days 3, 5 and 7) inhalations of PAF (each approximately 600 micrograms). The single inhalation of PAF (n = 8) caused an acute increase in Rrs (147 +/- 69%), an increase in BAL granulocytes, and a decrease in PC100 in four of eight animals that was moderate (greater than eight fold) in only one animal. The mean +/- s.e. change in log PC100 was -0.29 +/- 0.18. The multiple inhalations of PAF (n = 8) caused acute increases in Rrs (143 +/- 38%, 175 +/- 44% and 156 +/- 39%, respectively), an increase in BAL granulocytes, and a decrease in PC100 in four of eight animals that was moderate in two animals. The mean +/- s.e. change in log PC100 was -0.43 +/- 0.22.

Effect of Inhaled Platelet-Activating Factor on Bronchial Inflammation in Atopic Non-Asthmatic Subjects

We have investigated the effect of inhaled platelet-activating factor (PAF) on bronchial mucosal inflammation in 6 atopic non-asthmatic subjects in a double-blind, placebo-controlled, randomised and crossover study. On 2 study periods at least 4 weeks apart, fiberoptic bronchoscopy was performed 24 h after inhalation of either 200 micrograms PAF or methacholine (control) to obtain endobronchial biopsies. Immunocytochemistry using antibodies for trypase (AA1) and eosinophil cationic protein (EG2) was performed to enumerate mast cells and eosinophils, respectively, in the bronchial submucosa. Median values of AA1+ cells and EG2+ cells did not differ significantly after inhalation of PAF or control (23.8 vs. 39 and 6 vs. 8/mm2, respectively, PAF vs. control, non-significant). Our findings suggest that within 24 h of inhaling a bronchoconstrictor dose of PAF, this agonist does not induce bronchial hyperresponsiveness or mucosal inflammation in atopic non-asthmatic subjects. However, because of the small number of subjects studied, these preliminary data should be interpreted with caution.

Platelet-activating factor impairs mucociliary transport and increases plasma leukotriene B4 in man

We assessed the effect of inhaled platelet-activating factor (PAF) on tracheobronchial clearance, pulmonary function and blood pressure in seven healthy volunteers. After inhalation of 500 micrograms of PAF, retention of radioaerosol in ciliated airways measured at 4 h was 80% higher than in the control recording, and the clearance was reduced by 33% (p less than 0.005). Acetylsalicylic acid (ASA) did not abolish the phenomenon. PAF also decreased forced expiratory volume in one second (FEV1) by 16% (p less than 0.01), which was markedly attenuated by acetylsalicylic acid. The decrease in blood pressure after PAF (p less than 0.01) was not influenced by acetylsalicylic acid. Plasma leukotriene B4 (LTB4) was increased at 20 min after PAF inhalation (without and with ASA: mean 240 and 299 pg.ml.1, respectively) as compared to the baseline (144 and 166 pg.ml.1) and the values at 60 min after the challenge (133 and 178 pg.ml.1; p less than 0.05 and p less than 0.01, respectively). Only three out of seven subjects showed a bronchial hyperresponsiveness to methacholine measured 24 h after PAF. The PAF-induced reduction of mucociliary transport seems to be independent of cyclo-oxygenase products of arachidonic acid metabolism. These autacoids are, however, believed to contribute to the acute bronchial obstruction after PAF inhalation. In addition, inhaled PAF causes a transient increase in plasma LTB4.

Effects of PAF Antagonist, BN52021, on the PAF-, Methacholine-, and Allergen-Induced Bronchoconstriction in Asthmatic Children

Platelet-activating factor (PAF) is an inflammatory mediator capable of inducing protracted inflammation of the airways and bronchial hyperreactivity. Twenty-one asthmatic children were evenly divided into three groups and each group performed a double-blind, placebo-controlled and crossover study on the effect of aerosolized BN52021, a PAF antagonist, on the bronchoconstriction induced by PAF, methacholine, or specific allergen, respectively. One group of healthy children was included for comparison. Total WBC, neutrophils, and eosinophils were counted before and after PAF challenge. The results showed the following: (1) six of seven asthmatics and one of seven normal subjects gave a positive bronchial provocation with PAF; (2) in asthmatics, prior inhalation of BN52021 could inhibit the bronchoconstriction induced by PAF (6/6) and allergen (3/7), but not by methacholine; and (3) 5 min after inhalation of PAF, there was a marked decrease of peripheral blood eosinophils and neutrophils that could be inhibited by prior inhalation of BN52021 in normal subjects but not in asthmatics. These findings support the idea that PAF may be involved in the pathogenesis of bronchial asthma and PAF antagonist may have a role in the prevention and treatment of this disease.

Plasma Exudation into Airways Induced by Inhaled Platelet-Activating Factor: Effect of Peptidase Inhibition

1. To evaluate whether endogenous peptide release is involved in the airway responses to inhaled platelet-activating factor, we measured lung resistance and airway microvascular leakage in anaesthetized guinea pigs pretreated with inhalation of either saline or a combination of the peptidase inhibitors phosphoramidon (0.1 mmol/l: 60 breaths; 7.5 nmol), to inhibit neutral endopeptidase, and captopril (4.6 mmmol/l: 60 breaths; 350 nmol), to inhibit angiotensin-converting enzyme. 2. Airway microvascular leakage was determined by the albumin marker Evans Blue dye injected intravenously (20 mg/kg) before platelet-activating factor or sham challenge. 3. Inhaled platelet-activating factor induced a maximum increase in lung resistance (1.43 +/- 0.33 cmH2O s-1 ml-1) which was not significantly different after pretreatment with phosphoramidon and captopril (1.44 +/- 0.21 cmH2O s-1 ml-1). 4. Inhalation of platelet-activating factor caused a significant increase in extravasated Evans Blue dye at all airway levels, an effect which was not potentiated by peptidase inhibition. Similar results were obtained with dye extravasated into the airway lumen and absorbed by a filter paper placed on the tracheal mucosa. Approximately 11% of the total tracheal dye was found in the lumen. There was a high correlation between tracheal tissue and tracheal lumen Evans Blue dye (r = 0.91; P less than 0.001). 5. We found a significantly lower dry to wet weight ratio in proximal intrapulmonary airways of animals exposed to platelet-activating factor, suggesting that platelet-activating factor caused airway oedema at this airway level.(ABSTRACT TRUNCATED AT 250 WORDS)

567 The in-vitro effect of terfenadine on neutrophil chemotactic activity (NCA) and eosinophil chemotactic activity (ECA) after inhalation of platelet activating factor (PAF)

567 The in-vitro effect of terfenadine on neutrophil chemotactic activity (NCA) and eosinophil chemotactic activity (ECA) after inhalation of platelet activating factor (PAF)

Platelet-activating factor (PAF) induced rhinitis and involvement of PAF in allergic rhinitis in guinea pigs

The effects of inhaled PAF on the guinea pig nasal mucosa were investigated. Intranasal pressure (INP) was recorded as an index of intranasal resistance. To access the capillary premeability of nasal mucosa, exudation of Evans blue into the nasal lavage fluid was determined. Inhalations of histamine and PAF markedly and significantly increased INP and dye exudation into the nasal cavities. The two responses to PAF were about 20-fold and 70-fold stronger than those of histamine, respectively. A PAF antagonist, CV-3988, significantly antagonized both the PAF-induced increases in INP and dye exudation. Indomethacin and OKY-046 had no effect on the PAF-induced responses. FPL-55712 inhibited the PAF-induced increases in INP and dye exudation by 52% and 40%, respectively. Ovalbumin (OA) antigen challenge by inhalation to sensitized guinea pigs resulted in significant increases in both INP and dye exudation. These two responses to 30 mg/ml OA were inhibited by CV-3988 (10 mg/kg, i.v.) by 55% and 40%, respectively. From the above results, it is indicated that: 1) inhalation of PAF evokes rhinitis-like symptoms through activation of PAF receptors, 2) the PAF-induced rhinitis is, in a part, mediated by leukotrienes, and 3) PAF might be involved in allergic rhinitis.

The actions of GR32191B, a thromboxane receptor antagonist, on the effects of inhaled PAF on human airways

We investigated acute bronchoconstriction and changes in airway responsiveness to methacholine following the inhalation of platelet activating factor (PAF) in an open study of 12 non-asthmatic subjects. Ventilatory function was monitored using a flow rate at 30% of vital capacity (V30) and airway responsiveness was measured as PD40V30, i.e. the dose of metacholine causing a 40% fall in V30. PAF (3-422 micrograms) resulted in dose-related acute bronchoconstriction in 10 of the 12 subjects. There was no association between the airway responsiveness to PAF and to methacholine. Ten subjects showed some increase in airway responsiveness to methacholine 1 or 3 days following PAF. Overall, these changes were statistically significant (P less than 0.05) but were of small magnitude (geometric mean PD40V30pre-PAF = 457 micrograms; 24 hr after PAF = 259 micrograms; 72 hr after PAF = 258 micrograms) and variable: only seven subjects showing increased airway responsiveness on both day 1 and day 3 after PAF. Six subjects who appeared to show increases in airway responsiveness following PAF were re-studied with the inhaled PAF pre-medicated by either placebo or a specific thromboxane receptor antagonist (GR32191B) in a double-blind fashion. GR32191B did not reduce the acute bronchoconstriction due to PAF. In this part of the study, these six subjects did not show significant increases in airway responsiveness following the placebo pre-medicated PAF challenge and so no effect of the drug on airway responsiveness could be shown.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibitory effects of the new PAF acether antagonist WEB-2086 on pharmacologic changes induced by PAF inhalation in human beings

Recent research on asthma mediators has concentrated more and more on platelet-activating factor (PAF), which is one of the most potent bronchoconstrictors known thus far. Inhalant PAF challenge in healthy volunteers may provide a mean of testing PAF antagonists. The usefulness of the PAF provocation test in measuring the pharmacologic activity of a new PAF antagonist, WEB-2086, has been examined in 12 healthy volunteers in a double-blind, placebo-controlled, within-subject crossover study. PAF-induced immediate bronchoconstriction, slight hemodynamic changes, and PAF-related subjective side effects. Premedication with WEB-2086 (40 mg) completely prevented any increase in airway resistance after PAF inhalation, as well as development of most of the cardiovascular and side effects induced by PAF. The clear protection against PAF-induced pharmacologic effects can be explained by the specific PAF-antagonistic activity of WEB-2086. The method described in this article may be applied as a useful tool for looking at PAF-antagonistic activity in healthy volunteers.