Fluticasone propionate attenuates platelet-activating factor-induced gas exchange defects in mild asthma

Platelet-activating factor (PAF)-induced lung function abnormalities may be predominantly related to airway narrowing due to increased microvascular leakage 1–3. Like many other putative inflammatory mediators in the lung, PAF provokes vascular hyperaemia and/or engorgement, vasodilatation and increased vascular permeability within the airways, thereby facilitating exudation of protein-rich plasma and cells within and around the airway lumen 4, 5.

The predominant therapeutic site of inhaled glucocorticosteroids is in the airways. However, the potency of the topical glucocorticosteroids used for asthma is usually ranked by measuring local cutaneous vasoconstrictor effects when applied to the skin of healthy individuals 6. The clinical effects of glucocorticosteroids are mostly explained by their anti-inflammatory properties, which are time dependent. Beneficial short-term effects of inhaled glucocorticosteroids in asthma have recently been reported 7–9. High doses of inhaled flunisolide 7 and fluticasone 8 were superior to placebo (P) in the treatment of acute asthma in adults, and a vasoconstrictor effect of inhaled fluticasone propionate (FP) on bronchial blood flow has been demonstrated in mild intermittent asthmatics 9, 10. These effects may be enhanced by the increased vascularity of the bronchial wall, seen as part of the airway remodelling process in asthma 11, 12, and reduced by inhaled glucocorticosteroids 9, 10, 12.

The authors hypothesized that inhaled FP, a highly potent selective glucocorticosteroid with a low oral bioavailability 13, could prevent airway plasma leakage provoked by a laboratory-induced model of PAF challenge in patients with mild asthma, thereby leading to improvement in systemic, cellular, and lung function disturbances. Accordingly, the effects of a single high dose of inhaled FP on PAF-induced effects in patients with stable mild asthma were examined.

Methods

Results

Effects of fluticasone before platelet-activating factor

Table 1⇑ shows the characteristics and baseline functional measurements of all patients and table 2⇓ includes lung function and haemodynamic findings, peripheral cell counts and uLTE₄ concentrations before and after FP and vehicle administration. Compared with P, the inhalation of FP provoked an improvement in airway calibre, as assessed by mild favourable changes in FEV₁, either expressed as absolute values (p<0.04) or % pred (p<0.003), and R_rs (p<0.008) (fig. 1⇓ and table 2⇓). Likewise, inhaled FP increased peripheral blood neutrophils (p<0.004) but reduced eosinophil counts (p<0.008), without inducing changes in the concentrations of uLTE₄ (table 2⇓). The functional and cellular findings during P administration may be ascribed to the circadian rhythm. There were no differences in ventilatory, haemodynamic, and gas exchange indices between the morning set points after each pre-treatment.

• Download figure
• Open in new tab
• Download powerpoint

Fig. 1.—

Changes in the individual values of resistance of respiratory system (R_rs) (a and b) and forced expiratory volume in one second (FEV₁) (c and d) after placebo (○) and fluticasone propionate (•) pretreatment before platelet-activating factor challenge. —: mean values. p<0.008 comparing R_rs and p<0.04 comparing FEV₁ between placebo and fluticasone groups.

View this table:

• View inline
• View popup

Table 2—

Changes between placebo and fluticasone propionate before platlet-activating factor challenge

Effects of platelet-activating factor after vehicle

Effects of PAF after vehicle are shown in table 3⇓ and figure 2⇓. Ten patients noticed facial flushing, 11 felt shortness of breath, and six coughed immediately after PAF challenge. Five min after PAF, R_rs increased by 73% (from 3.23±0.18 to 5.60±0.45 cmH₂O·L⁻¹·s, p<0.01), P_a,O2 decreased by 23% (from 96±4 to 74±2 mmHg), P_A-a,O2 increased (from 8±3 to 26±3 mmHg, p<0.001), and peripheral blood neutrophils decreased (from 2.76±0.30 to 1.66±0.36×10⁹ L⁻¹, p<0.01). This neutropenia was followed by a rebound neutrophilia at 15 and 45 min (4.47±0.58 and 4.82±0.69×10⁹ L⁻¹, respectively, p<0.05). Both ventilatory and haemodynamic variables and P_a,CO2 and arterial pH remained unchanged.

• Download figure
• Open in new tab
• Download powerpoint

Fig. 2.—

The time course of resistance of a) the respiratory system (R_rs), b) oxygen tension in arterial blood (P_a,O2) and c) the alveolar-arterial oxygen pressure gradient (P_A-a,O2) at baseline (BL) and at 5, 15, and 45 min after inhaled platelet-activating factor (PAF). ○: pretreatment with placebo; •: pretreatment with flucticasone propionate; arrows: PAF challenge. *: p<0.05 between placebo and fluticasone propionate.

View this table:

• View inline
• View popup

Table 3—

Changes induced by platlet-activating factor after placebo (P) and fluticasone propionate (FP) pretreatments

Effects of platelet-activating factor after fluticasone propionate

Effects of PAF after FP are shown in table 3⇑ and figure 2⇑. Pretreatment with FP did not modify or abolish PAF-induced systemic effects: 10 patients noticed facial flushing, 11 shortness of breath, and three cough. Inhaled FP, as compared with vehicle, enhanced the PAF-induced decrease in circulating neutrophils at 5 min (from 3.93±0.40 to 1.71±0.43×10⁹ L⁻¹; FP −57%; P -40%; p<0.05), whereas the rebound neutrophilia observed at 15 and 45 min (5.20±0.61 and 5.56±0.67×10⁹ L⁻¹, respectively) did not differ from that shown after P. Moreover, FP inhalation exhibited modest but significantly greater P_a,O2 (FP 93±4 mmHg; P 83±4 mmHg; p<0.01) (fig. 3⇓) and lower P_A-a,O2 (FP 11±3 mmHg; P 18±3 mmHg; p<0.02) values at 45 min, as compared with P. Compared to baseline (±1 mmHg) (fig. 3⇓), mean P_a,O2 after P was reduced in eight patients (−18.3±4.3 mmHg), was similar in two patients (−0.9 mmHg), and increased in the remaining patient (4.4 mmHg). Conversely, P_a,O2 after FP was reduced in five patients (−11.7±5.9 mmHg) and increased in the other six (5.0±0.9 mmHg). Remarkably, there were no differences in the increases in R_rs after PAF between the two interventions. The significant increase in uLTE₄ concentration observed after PAF inhalation in the FP arm (from 355±104 to 1,608±352 pg·mg⁻¹) was not different from that measured after P (from 305±34 to 1,421±401 pg·mg⁻¹, p<0.0001).

• Download figure
• Open in new tab
• Download powerpoint

Fig. 3.—

Individual changes in oxygen tension in arterial blood (P_a,O2) after placebo (○) and fluticasone propionate (•), before (and after each pretreatment) and 45 min after platelet-activating factor challenge. —: mean values. p<0.01 comparing placebo and fluticasone.

Discussion

In this study, three main effects of administration of a single high dose of inhaled FP in patients with mild intermittent asthma were observed. Firstly, FP to some degree prevented the diurnal fall in bronchial tone. Secondly, immediately after PAF challenge, there was a more pronounced reduction in circulating neutrophils without differences in the subsequent rebound neutrophilia. Finally, FP attenuated gas-exchange defects by the end of PAF challenge, as shown by a greater recovery of arterial oxygenation, without modifying the bronchoconstrictor response.

In this study, the effects of FP 12 h after inhalation were investigated following a previous preliminary study that examined the inhalation of low-to-high doses of budesonide (≤1,600 µg) in patients with mild asthma 18. In the study by Le Merre et al. 18, the inhaled glucocorticosteroid improved lung function maximally at 12–14 h. In addition, the authors own preliminary studies, including inert gas measurements, showed no effects of FP when studied at 2 h, using 2 and 6 mg, and 6 h, using 6 mg (data not shown). There is evidence of diurnal variation in FP pharmacokinetics, with higher than expected plasma drug concentrations in the morning than in the evening 19. In this study, a high dose of FP (6 mg) was used, which was likely to contribute to systemic levels. Challenge with PAF, a mediator that may be involved in the pathogenesis of asthma, causes moderate-to-severe gas exchange deterioration 1–3, 20, similar to that seen in spontaneously-occurring acute asthma. This indicates that the principal mechanism of PAF-induced arterial hypoxaemia, i.e. ventilation perfusion inequalities, could result more from increased vascular permeability than from bronchoconstriction per se 2, 20.

The authors suggest that the three principal effects of FP observed in the current study may be related to the pharmacological properties of inhaled glucocorticosteroids.

Firstly, the bronchodilator effect before PAF challenge could be due to the anti-inflammatory effects of the drug exerted on the bronchial mucosa, although a vasoconstrictor effect on bronchial blood flow cannot be disregarded (see later) 9, 10.

Secondly, FP enhanced the peripheral neutropenia usually caused by PAF. The authors surmize that FP before PAF facilitated the release of neutrophils from the bone marrow and that these new neutrophils might be less mature and more rigid, i.e. less deformable, and possibly larger than neutrophils that have been circulating. All other things being equal, this would favour a more pronounced retention in the lung after PAF challenge 21, 22. Inhaled PAF provokes considerable airway neutrophilia in asthmatics 21, 23 and neutrophilic airway inflammation has been shown to be predominant in persistent asthma 24. However, glucocorticosteroids do not reduce neutrophilic airway disease inflammation 25 and airway neutrophilia could even persist through glucocorticosteroid-induced inhibition of neutrophil apoptosis 26. Thus, FP is unlikely to modulate the PAF-induced airway response mediated in part by the release of leukotrienes 15.

Thirdly, the authors hypothesize that the late PAF-induced pulmonary gas exchange amelioration in the FP arm may reflect a predominant vasoconstrictor effect on the pulmonary circulation, possibly facilitating a better alveolar ventilation to pulmonary blood flow balance. As shown in previous studies with other interventions 2, 15, 16, the lack of an earlier beneficial P_a,O2 response after PAF may be due to the intense severity of lung function abnormalities at the nadir of the challenge, not offset by the high doses of FP given. It has been convincingly shown that ventilation perfusion mismatch instantly caused by PAF, steadily recovers as the effects of PAF vanish, with a trend toward baseline values by 45 min 1–3, 15, 16. The latter finding is at variance with the attenuation of arterial hypoxaemia shown at the end of this study in the FP arm. By contrast, PAF-induced systemic effects and increases in both R_rs and uLTE₄ concentrations were not affected throughout the study period, without differences between the two interventions. These negative findings may indicate that FP could not exert a beneficial effect against PAF-induced airway inflammation, which can be mediated, at least in part, by an ongoing endogenous release of leukotrienes 15. However, complementary bronchial vasoconstriction cannot be overlooked 9, 10, as the methodology used for the assessment of PAF-induced increases in total R_rs may be less sensitive than gas exchange measurements in detecting an effect on airway vasculature.

The proposed mechanisms of inhaled glucocorticosteroids include upregulation of selective β-adrenergic receptors, vasoconstriction of the mucosa and decreased wall oedema within the airway 27. However, the rapid onset of the clinical response in some of these clinical studies 7, 9 would indicate that some beneficial effects of glucocorticosteroids may occur very rapidly, while other effects may occur very slowly, requiring a minimum of 6–12 h after medication 28. McFadden 29 postulated that the effects of flunisolide in patients with acute asthma 7 could result from a nonspecific generic phenomenon common to topical steroids, thereby causing substantial vasoconstriction in the larger airways and modifying, at least in part, some of the pathophysiological components of airway narrowing in bronchial asthma. A transient short-term vasoconstrictor effect in the airway mucosa has recently been demonstrated in mild intermittent asthmatics, after moderate-to-high doses of inhaled FP 9 and after a 2-week course of moderate doses of FP 10. Glucocorticoid-induced bronchial vasoconstriction could be related to noradrenaline uptake inhibition by nonneuronal cells, that may facilitate increased noradrenaline concentration at α-adrenergic receptors 30.

However, the precise pathogenic mechanism through which inhaled glucocorticosteroids cause bronchial vasoconstriction remains to be elucidated. It has been postulated that this vascular response may reflect a nongenomic mode of action 9, 27 related to stimulation of noradrenergic neurotransmission. However, glucocorticosteroids do not exhibit direct noradrenergic properties. Airway mucosal blood flow is increased in stable asthmatics 9, 10, 12, 31. These observations indicate that inhaled glucocorticosteroids, especially at higher doses, may downregulate airway wall vascularity 12 and restore downregulation of β-adrenergic agonist-mediated response in patients with asthma 9, 10, hence reflecting their anti-inflammatory properties 10, 12.

In conclusion, the authors have shown that a single administration of a high dose of inhaled fluticasone propionate facilitates a better recovery of decreased oxygen tension in arterial blood in a laboratory-induced model of bronchoconstriction caused by platelet-activating factor in mild asthmatics. High doses of this inhaled glucocorticosteroid may attenuate gas exchange defects provoked by platelet-activating factor, by inducing a vasoconstrictor effect within the pulmonary circulation, similar to that shown with a lower dose of fluticasone propionate in the bronchial blood flow compartment. Even though there is an effect of fluticasone propionate on wall oedema and/or bronchial vascular engorgement in peripheral airways with or without redistribution of platelet-activating factor, deposition within the airways cannot be overlooked.