Inhibition of PAF-induced Gas Exchange Defects by Beta-adrenergic by aos51173


									Inhibition of PAF-induced Gas Exchange Defects by
Beta-adrenergic Agonists in Mild Asthma Is Not
Due to Bronchodilation
Serveis de Pneumologia i Al.lèrgia Respiratòria, Departament de Medicina, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain;
and National Heart and Lung Institute, Imperial College, School of Medicine, London, United Kingdom

               Salbutamol inhibits neutropenia, increased airway resistance, and gas exchange abnormalities pro-
               voked by platelet-activating factor (PAF) challenge in normal persons. To further explore the intrigu-
               ing dissociation between spirometric abnormalities and gas exchange defects shown in patients with
               asthma, we investigated whether the salbutamol-induced improvement in gas exchange distur-
               bances after PAF is the result of bronchodilation by comparing this effect with that of ipratropium
               bromide. We hypothesized that ipratropium bromide, an anticholinergic agent without vascular ef-
               fects, should block PAF-induced bronchoconstriction but not interfere with its systemic, neutropenic,
               and gas exchange effects. We studied eight nonsmokers with mild asthma (26                2.0 SE yr of age)
               who, prior to PAF challenge (18 g), inhaled either ipratropium bromide (80 g) or salbutamol
               (300 g) in a randomized, double-blind, crossover fashion 1 wk apart. Peripheral blood neutrophils,
                                                                                                        · ·
               respiratory system resistance (Rrs), arterial blood gases and ventilation-perfusion (VA/Q ) inequalities
               were measured 5, 15, and 45 min after PAF. Compared with pretreatment with salbutamol, ipratro-
               pium bromide also blocked the increase of respiratory system resistance (Rrs) but did not prevent fa-
               cial flushing and neutropenia (p 0.03) at 5 min nor the decrease of PaO2 (p 0.08 and 0.05), the in-
                                                                          · ·
               crease of AaPO2 (p 0.02 each), and the deterioration of VA/Q relationships (p 0.05 each) at 5 and
               15 min, respectively. This functional pattern was similar to that observed previously in normal sub-
               jects and in nonpremedicated asthmatic patients after PAF, with return to baseline values at 45 min.
               By contrast, salbutamol blocked PAF-induced increased Rrs, in addition to all the other PAF-induced
               abnormalities. These findings indicate that, in patients with mild asthma, salbutamol inhibits PAF-
               induced neutropenia and gas exchange abnormalities by mechanisms involving other than airway
               smooth muscle narrowing, possibly by acting on both the bronchial and pulmonary circulations. Díaz
               O, Barberà JA, Marrades R, Chung KF, Roca J, Rodriguez-Roisin R. Inhibition of PAF-induced
               gas exchange defects by beta-adrenergic agonists in mild asthma is not due to bronchodila-
               tion.                                                                 AM J RESPIR CRIT CARE MED 1997;156:17–22.

Platelet-activating factor (PAF) is a potent ether-linked phos-                          characterized by an increased dispersion of pulmonary blood
pholipid mediator of inflammation that is considered to have                             flow, including the development of low ventilation-perfusion
                                                                                            · ·                                             · ·
a role in the pathogenesis of bronchial asthma and other pul-                            (VA/Q) areas, identical to the entire spectrum of VA/Q inequal-
                                                                                                                                                     · ·
monary disorders (1, 2). We have shown that PAF induced or                               ities seen in patients with bronchial asthma (5). Although VA/Q
worsened gas exchange abnormalities in normal subjects (3)                               mismatching in patients with asthma is akin to airway narrow-
and in patients with mild asthma (4). These disturbances were                            ing by both inflammation and bronchoconstriction, the precise
                                                                                                                 · ·
                                                                                         mechanism by which VA/Q inequalities may occur still remains
                                                                                                                            · ·
                                                                                         elusive. We suggested that the VA/Q defects could be related
(Received in original form October 28, 1996 and in revised form March 7, 1997)           to an increased tracheobronchial vascular permeability induced
Supported by Projects 94/0986 from the Fondo de Investigación Sanitaria (FIS)            by PAF, therefore supporting the notion that PAF may play a
and 1995 SGR 00446 from the Comissionat per a Universitats i Recerca de la
Generalitat de Catalunya, and a Training Grant (Formación de Investigadores,
                                                                                         key role as a putative mediator of inflammation in airways (3, 4).
Programa de Cooperación Científica con Iberoamérica) from the Ministerio de                  Previous studies in asthmatic patients have consistently
Educación y Ciencia, Spain.                                                              shown a poor correlation between the behavior of reduced
Dr. Díaz is Associate Professor of Universidad Pontificia de Santiago de Chile, Chile.   maximal expiratory airflow rates and abnormal pulmonary gas
Correspondence and requests for reprints should be addressed to J. Roca, M.D.,           exchange, namely, arterial blood gases and their major intra-
                                                                                                                      · ·
Servei de Pneumologia i Al.lèrgia Respiratòria, Hospital Clínic, Villarroel, 170,        pulmonary determinant, VA/Q imbalance, in individual pa-
08036-Barcelona, Spain.                                                                  tients and also within clinically similar asthma patients’ cate-
Am J Respir Crit Care Med Vol. 156. pp. 17–22, 1997                                      gory, such that it can be extended across the full constellation
18                                                      AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE                               VOL. 156        1997

of asthma severity (5, 6). Conceivably, these intriguing find-                                                     TABLE 1
ings reflect two different pathophysiologic phenomena and                         ANTHROPOMETRIC AND BASELINE FUNCTION DATA ON
concur with the hypothesis that decreased spirometric indices                      IPRATROPIUM BROMIDE AND SALBUTAMOL STUDIES*
reflect reduction of airway caliber in larger and middle-size              Age, yr                                     26 2
bronchi, whereas pulmonary gas exchange disturbances pre-                  Sex, F/M                                       5/3
dominantly refer to structural changes in distal small airways             Height, cm                                 165 3
(6). Thus, the latter changes could be more preferentially re-             Weight, kg                                  63 3
lated to airway inflammation rather than to airflow obstruction            FEV1, L                                     3.4 0.3 (93        3% pred)
by itself. Notwithstanding, cause and effect relationship will be          FEV1/FVC, %                                 80 1.5
                                                                           PD20, mol                                 0.39 0.12
very difficult to establish in humans.
    Salbutamol, a short-acting beta-adrenergic agonist, inhibits                                                  Ipratropium Bromide                    Salbutamol
PAF-induced increased airway resistance and the systemic                   Rrs, cm H2O/L/s                           3.36     0.31                       3.12     0.28
(cough, facial flushing, and feeling of warmth), cellular (pe-             VE, L/min                                  7.5     0.8                         7.0     0.4
ripheral blood neutropenia), and gas exchange (impaired arte-              RR, /min                                    15     1.6                          15     0.9
                         · ·                                               Ps, mm Hg                                   83     5                            86     3
rial oxygenation and VA/Q imbalance) effects in normal sub-                 ·
                                                                           QT, L/min                                  5.6     0.2                         6.2     0.4
jects (7, 8). We postulate that these effects of salbutamol could          HR, /min                                    77     5                            81     6
be related preferentially to an inhibition of PAF-induced pre-             Neutrophils, 109/L                        3.56     0.35                       3.67     0.46
capillary and postcapillary endothelial constriction in the bron-          PaO2, mm Hg                               101      3                          101      2
chial microcirculation (9, 10), although its potent relaxant effect        PaCO2, mm Hg                                35     1                            36     1
on airway smooth muscle cannot be overlooked. If so, an anti-              pH                                        7.44     0.01                       7.44     0.01
                                                                           AaPO2, mm Hg                                13     2                             9     1
cholinergic agent devoid of vascular effects such as ipratro-                           ·
                                                                           Shunt, % of QT                             0.0     0.1                         0.3     0.4
pium bromide should prevent PAF-induced bronchoconstric-                         · ·
                                                                           Low VA/Q, % of QT
                                                                                                                      1.0     0.4                         0.3     0.2
tion but not interfere with its systemic, cellular, and gas exchange       Log SDQ                                   0.59     0.07                       0.46     0.05
effects. The present study was undertaken to test this hypothe-            Log SDV                                   0.49     0.05                       0.43     0.05
sis by assessing the cellular, lung mechanical, and gas exchange           Dead space, % of VA                         27     2.8                          29     3.9
responses to PAF after ipratropium bromide (80 g) and sal-                 DISP R-E*                                 3.79     0.67                       2.80     0.61
butamol (300 g) given by inhalation in patients with mild                     Definition of abbreviations: PD20 provocative dose of methacoline producing a 20%
asthma.                                                                    fall in FEV1; Rrs total respiratory system resistance; V E minute ventilation; RR re-
                                                                           spiratory rate; Ps    mean systemic arterial pressure; QT       cardiac output; HR    heart
                                                                           rate; AaPO2 alveolar-arterial PO2 difference; Shunt % of QT to lung units with V A/Q
                                                                                                                                                                  · ·
                                                                                                  · ·                                  · ·
                                                                                                                · T to lung units with V A/Q ratios 0.1; Log SDQ
METHODS                                                                    ratios 0.005; Low V A/Q % of Q
                                                                           dispersion of the perfusion distribution; Log SDV       dispersion of the ventilation distri-
Patients                                                                                                ·                     · ·
                                                                           bution; Dead space % V A to lung units with V A/Q ratios 100; DISP R-E* overall
                                                                                      · ·
                                                                           index of V A/Q inequality.
Eight nonsmokers with mild asthma were recruited for the study (Table         * Values are mean SE. Predicted values for forced spirometry were taken from Ref-
1), which was approved by the Ethical Committee of Hospital Clínic.        erence 11.
All subjects gave informed written consent after the purpose, risks, and
potential benefits of the study were explained to them. Inclusion crite-
ria were: no respiratory infection or exacerbation of asthma within the
preceding 6 wk; FEV1         70% predicted and positive methacholine       steady-state conditions after PAF challenge was demonstrated by sta-
bronchial challenge (PD20 4.0 mol); maintenance therapy with aero-         bility ( 5%) of both ventilatory and hemodynamic variables, and by
sol short-acting beta-adrenergics and/or inhaled corticosteroids, but no   the close agreement between duplicate measurements of mixed ex-
previous treatment with oral steroids; absence of any systemic or car-     pired and arterial O2 and CO2 (within 5%). These conditions were
diopulmonary disease other than asthma.                                    met in all patients throughout the whole period of study.
                                                                               Total resistance of the respiratory system (Rrs) was measured by
Measurements                                                               the forced oscillation technique and its analysis restricted to 8 Hz
Blood samples were collected anaerobically through a catheter in-          (3, 4). A three-lead electrocardiogram, heart rate (HR), and systemic
serted into the radial artery. Total white cell counts in arterial blood   pressure (Ps) were continuously recorded throughout the whole study
were measured with a Technicon H.1™ System (Technicon, Tarry-              (HP 7830A Monitor and HP 7754B Recorder; Hewlett-Packard,
town, NY). Arterial PO2, PCO2, and pH were analyzed in duplicate us-       Waltham, MA).
ing standard electrodes (IL 1302; Instrumentation Laboratories, Mil-
ano, Italy). Hemoglobin concentration was measured by a Co-oximeter        Study Design
(IL 482; Instrumentation Laboratories). Oxygen uptake (VO2) and CO2        A randomized double-blind crossover design was used to compare the
production (VCO2) were calculated from mixed expired O2 and CO2            effect of salbutamol with that of ipratropium bromide on PAF-
concentrations measured by mass spectrometry (Multigas Monitor             induced effects, with subjects breathing room air and seated in an
MS2; BOC-Medishield, London, UK). Minute ventilation (VE) and              armchair. Medication was withheld for 12 h before arrival to the labo-
respiratory rate (RR) were measured using a calibrated Wright spirom-      ratory. Once the inert gas solution had been infused for at least 45 min
eter (Respirometer MK8; BOC-Medical, Essex, UK). The AaPO2 was             to allow for the establishment of adequate steady-state conditions,
calculated according to the alveolar gas equation using the measured       baseline measurements were performed. All subjects were challenged
respiratory exchange ratio (R). The multiple inert gas elimination tech-   on two occasions 1 wk apart with inhaled PAF 30 min after the admin-
                                                    · ·                    istration of either ipratropium bromide (two puffs         80 g) or sal-
nique (MIGET) estimated the distributions of VA/Q ratios without
sampling mixed venous inert gases in the customary manner, a modality      butamol (three puffs 300 g), using a regular metered-dose inhaler
that can be used with similar accuracy (12) in all but one patient. With   with an approximately 1-L holding chamber, one puff at a time, and a
this approach cardiac output needs to be directly measured by dye dilu-    set of measurements was taken 15 min later. It has been shown that
tion technique (DC-410; Waters Instruments Inc., Rochester, MN) us-        80% of the maximal bronchodilation produced by ipratropium bro-
ing a 5-mg bolus of indocyanine green injected through a catheter          mide can be achieved with a cumulative dose of 72 g (13). Patients
placed percutaneously in a vein of the arm while mixed venous inert        were challenged with PAF (C16) (1-0-Hexadecyl-2-acetyl-sn-glycero-
gas concentrations are computed from mass balance equations (12).          3-phosphocholine) (18 g) (Novabiochem AG, Lucerne, Switzerland).
The duplicate samples of each set of measurements were treated sepa-       Duplicate measurements were taken at 5, 15, and 45 min after PAF in-
rately, the final data resulting in the average of variables determined    halation, as described previously (6). All sets of measurements consisted
             · ·                                                           of the following steps in sequence: inert gas sampling and ventilatory
from both VA/Q distributions at each point in time. Maintenance of
Díaz, Barberà, Marrades, et al.: PAF, Bronchodilators, and Gas Exchange in Asthma                                                                       19

                                                                             TABLE 2
                                             BEFORE AND 5 MIN AFTER PAF CHALLENGE*

                                                              Ipratropium Bromide                                          Salbutamol

                                                    (before PAF )                (after PAF )              (before PAF )                 (after PAF )

                Rrs, cm H2O/L/s                     2.76    0.3                3.27     0.3                2.63    0.2                  2.74    0.2
                VE, L/min                            7.6    0.9                 8.2     1.0                 7.3    0.4                   7.3    0.7
                RR, /min                              15    1.6                  16     1.6                  15    0.9                    15    1.0
                Ps, mm Hg                             83    5                    82     4                    87    3                      86    3
                QT, L/min                            5.3    0.3                 5.5     0.4                 6.9    0.4                   6.5    0.5
                HR, /min                              77    5                    76     5                    81    6                      84    7
                Neutrophils, 109/L                  3.74    0.35               1.67     0.39†              3.62    0.44                 3.03    0.58†
                PaO2, mm Hg                         101     4                    87     5                  101     3                      97    5
                PaCO2, mm Hg                          36    1                    35     1                    37    1                      36    1
                pH                                  7.44    0.01               7.43     0.03               7.44    0.01                 7.44    0.04
                AaPO2, mm Hg                          13    3                    30     5†                   11    2                      16    4†
                Shunt, % of QT                       0.0    0.1                 0.0     0.1                 0.3    0.4                   0.2    0.1
                      · ·        ·
                Low VA/Q, % of QT                    1.6    1.0                 4.6     2.0                 0.5    0.5                   1.9    1.8
                Log SDQ                             0.57    0.09               0.87     0.11†              0.51    0.07                 0.57    1.0†
                Log SDV                             0.47    0.04               0.57     0.05               0.56    0.07                 0.50    0.04
                Dead space, % of VA                   29    2.5                  26     3.8                  27    4.0                    30    3.1
                DISP R-E*                           3.46    0.80               6.35     1.36†              3.69    0.75                 3.77    0.95†

                  For definition of abbreviations, see Table 1.
                  * Values are mean SE. For p values, see RESULTS.
                    Significant changes between ipratropium bromide and salbutamol after PAF inhalation.

recordings; respiratory gas sampling; hemodynamic measurements;                       5 min; in addition, PaO2 showed a trend to decrease (from 101
sampling for circulating white blood cells; measurements of Rrs.                      4 to 87 5 mm Hg) (p 0.08) at 5 min, which persisted at 15
                                                                                      min (to 93      5 mm Hg) (p     0.05), whereas AaPO2 increased
Statistics                                                                            markedly (from 13 3 to 30 5 mm Hg and to 24 3 mm Hg)
Results are expressed as mean SE. Changes in neutrophils, Rrs, ar-                    at 5 and 15 min, respectively (p 0.02 each), returning to base-
                        · ·
terial blood gases, and VA/Q inequalities were assessed by an analysis                line values at 45 min. These findings were paralleled by a con-
of variance (ANOVA) model appropriate to the two-period two-treat-                                 · ·
                                                                                      siderable VA/Q deterioration, essentially illustrated by a
ment crossover design, to determine the effect of ipratropium bro-                    marked increase of the dispersion of pulmonary blood flow
mide compared with that of salbutamol, hence allowing for intraindi-                  (log SDQ) (from 0.57 0.09 to 0.87 0.11 and 0.73 0.10) at
vidual comparisons at each time point. Homoscedasticity was obtained
                                                                                      5 and 15 min, respectively (p      0.04 each) along with an in-
by logarithmic transformation. This statistical approach was identical                                                 · ·
to that used in our previous studies (7, 8). Significance was set at p                crease of an overall index of VA/Q inequality (DISP R-E*)
0.05 in all instances.                                                                (the combined dispersion of both blood flow and ventilation
                                                                                      distributions corrected for dead space [14]) (from 3.46 0.80
                                                                                      to 6.35 1.36 and 4.91 1.09) at 5 and 15 min, respectively
                                                                                      (p 0.05 each), to return to baseline values at 45 min. Individ-
Baseline Data and Effects of Inhaled Ipratropium and                                  ually, all patients pretreated with ipratropium bromide had a
Salbutamol before PAF                                                                 deterioration in pulmonary gas exchange after PAF, whereas
Baseline measurements for all patients were similar to those re-                      in all but one patient, PAF-induced gas exchange defects were
ported in our previous investigation (7), without differences be-                     prevented after salbutamol (Figure 2). Similarly, the first mo-
                                                                                                     · ·                            · ·
tween ipratropium bromide and salbutamol studies (Tables 1                            ment of the VA/Q distributions (the mean VA/Q ratio of the
and 2 and Figure 1). Compared with ipratropium bromide, how-                          ventilation distribution, V) increased (from 1.28        0.12 to
                                            ·                                         1.42 0.08) at 15 min (p 0.02) after ipratropium bromide.
ever, salbutamol produced an increase of QT (from 6.2 0.4 to
6.9 0.4 L/min) (p 0.02) before PAF inhalation, whereas the                                Overall, the changes observed in neutrophils and both res-
                      · ·                           · ·                               piratory and inert gas exchange descriptors after ipratropium
first moment of the VA/Q distribution (the mean VA/Q ratio of
the perfusion distribution, Q) decreased (from 0.78       0.06 to                     bromide were similar to those previously detected in unpre-
0.70 0.05) (p 0.03), an effect also shown previously in nor-                          medicated patients with asthma (4), or in normal subjects
mal subjects after they had received salbutamol (7).                                  unpretreated (3) or pretreated with saline (vehicle) (7, 8), in-
                                                                                      dicating that ipratropium bromide had no effect on the PAF-
Effects of Ipratropium Bromide and Salbutamol after PAF                               induced abnormalities. By contrast, salbutamol prevented all
                                                                                      PAF-induced functional defects, including systemic and neu-
Compared with pretreatment with salbutamol, after ipratro-
                                                                                      trophil changes. Ventilatory and hemodynamic variables and
pium bromide there were no significant differences in Rrs after
                                                                                      all the other gas exchange indices remained unchanged be-
PAF challenge, indicating that both agents were efficacious in
                                                                                      tween studies after PAF challenge.
blocking the expected PAF-induced increase of Rrs (Table 2
and Figures 1 and 2). However, after pretreatment with ipra-
tropium bromide six subjects noticed facial flushing, and five
coughed immediately; by contrast, after salbutamol only one                           The unique finding of this study is that, in patients with mild
patient had facial flushing. On the other hand, after pretreat-                       asthma, ipratropium bromide administered at a maximal bron-
ment with ipratropium bromide there was significant neutrope-                         chodilating dosage had a protective effect on bronchoconstric-
nia (from 3.74     0.35 to 1.67   0.39    109/L) (p    0.03) at                       tion but not on the systemic, neutropenic, and pulmonary gas
20                                        AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE                 VOL. 156   1997

     Figure 1. Mean SE values showing peripheral neutrophils, resistance of the respiratory system, alveolar-
     arterial PO2 difference, and ventilation-perfusion mismatching (expressed as DISP R-E*, dimensionless [14])
     after PAF challenge in the two groups. Closed symbols       pretreated with ipratropium bromide (IB); open
     symbols      pretreated with salbutamol (s) at baseline (BL), at 15 min after bronchodilators, and at 5, 15,
     and 45 min. Asterisks denote significance (see RESULTS for p values).

     Figure 2. Individual time courses of alveolar-arterial P O2 and ventilation-perfusion inequalities (expressed
     as DISP R-E*, dimensionless [14]) (n    7) after inhaled PAF with pretreatment with inhaled ipratropium
     bromide or with salbutamol at baseline (BL), at 15 min after bronchodilators, and at 5, 15, and 45 min
     (see Table 1 and Figure 1 for other abbreviations).
Díaz, Barberà, Marrades, et al.: PAF, Bronchodilators, and Gas Exchange in Asthma                                                                21

exchange responses provoked by PAF challenge. By contrast,           bronchial tree (18). PAF may also act directly on postcapillary
salbutamol prevented all PAF-induced lung function distur-           venular endothelial cells in the bronchial microcirculation (9,
bances, including facial flushing and peripheral neutropenia.        10). Salbutamol could also prevent the ensuing release of other
Our findings complement and extend our previous investiga-           mediators into the pulmonary circulation with potential re-
tions in normal subjects that pretreatment with inhaled sal-         gional vasodilator effects that can disturb the matching of ven-
butamol suppressed all PAF-induced effects (3, 7, 8). It is of       tilation and perfusion at the alveolar level, hence antagonizing
                                                                               · ·
note that a lower dose of salbutamol (200 g) had no effect on        further VA/Q disturbances. It is of note that these potential
the flushing, neutropenia, and bronchoconstriction observed          vasodilator effects of salbutamol on the bronchial and pulmo-
                                                                                                          · ·
after a higher dosage of inhaled PAF in normal subjects (15).        nary circulations, precluding the VA/Q deterioration by PAF
          · ·                                                                                                                    · ·
    The VA/Q mismatching, expressed as an increase of the dis-       as alluded to above, do not contend with their impact on VA/Q
persion of pulmonary blood flow (log SDQ), observed in the           worsening in patients with asthma. We have previously shown
current study in the asthmatic patients premedicated with ip-        that inhaled salbutamol (total doses, 600 and 300 g) does not
                                                                                            · ·
ratropium bromide was quantitatively similar to that shown in        alter the underlying VA/Q status in patients with either severe
healthy subjects (3, 7) in whom a higher dose (24 g) of in-          acute (19) or persistent (20) asthma, respectively.
haled PAF was used and to that in patients with mild asthma              Likewise, the beneficial role of salbutamol in preventing
inhaling a lower dose (12 g) of PAF (4); likewise, the falls in      PAF-induced neutrophil sequestration in the lungs may indi-
peripheral blood neutrophil counts were of a similar order of        cate an antiedema property that may result from inhibition of
magnitude to those of normal subjects (3, 8) or even greater         PAF-induced inflammation in airway wall, possibly amplified
than in asthmatics (4). In the current study and in the previous     by its potent relaxant effect on conducting airways. This inter-
one (4), in patients with asthma, however, inhaled PAF was           pretation is consistent with the inhibition by 2-adrenergic ag-
qualitatively detrimental to pulmonary gas exchange, provok-         onists of the increased tracheobronchial microvasculature per-
      · ·
ing VA/Q defects in a pattern similar to that commonly ob-           meability provoked by PAF (21, 22) and also by histamine
served in patients with moderate to severe asthma (5). In the        (23). Indirect evidence (22) suggests, however, that the protec-
                                     · ·
present study, the deterioration of VA/Q relationships resulted      tive role of salbutamol on gas exchange may be more related
mainly from an increase in the dispersion of pulmonary blood         to an inhibition of a PAF-induced venoconstrictor effect on
                                                      · ·
flow caused by the development of poorly ventilated VA/Q units,      the airway microcirculation (23–27). Moreover, salbutamol
akin to the underlying pathophysiology of bronchial asthma (5).      causes vasodilatation that can increase the postmicrovascular
Our data are, however, at variance with those obtained by Smith      to premicrovascular resistance ratio of the bronchial circula-
and coworkers (16) in normal subjects and in asthmatics, in          tion, thereby decreasing the hydrostatic pressure and subse-
whom pretreatment with atropine paradoxically enhanced PAF-          quent plasma exudation (28). The reduction of hydrostatic
                                                   · ·
induced bronchoconstriction. Collectively, these VA/Q findings       pressure in the airway capillary network could decrease the
after salbutamol and ipratropium bromide strengthen the view         degree of airway submucosal and adventitial swelling, thereby
that bronchoconstriction and gas exchange disturbances in pa-        preventing the narrowing of the caliber in distal airways, re-
tients with asthma are related to two different pathophysiologic     sulting in pulmonary gas exchange abnormalities. Salbutamol
components. Thus, a bronchodilator acting predominantly on           would have thus enhanced the ability of endothelial cells to ei-
larger airways and devoid of other effects such as ipratropium       ther minimize and/or close PAF-induced interendothelial gap
bromide prevented PAF-induced increased resistance of the            junctions by facilitating their relaxation.
                                                 · ·
respiratory system only without influencing VA/Q deteriora-              If pretreatment with salbutamol has a protective effect on
tion or the neutropenic and systemic responses. By contrast,         the transient sequestration of neutrophils in the pulmonary cir-
salbutamol, a bronchodilator with potent vasodilator effects,        culation produced by PAF, it may reduce the activation of these
blocked all PAF-induced effects, possibly by modulating ab-          cells in the lungs and the subsequent cascade of other released
normal vascular permeability-increasing mediators that oper-         mediators that may also play a role in the PAF-induced pulmo-
ate directly on the venular endothelium. In this respect, gas        nary function abnormalities. Both facial flushing and cough in-
exchange measurements can emerge as a better tool than any           duced by PAF have been attributed to the release of by-prod-
other lung function test to more accurately identify the patho-      ucts, possibly derived from neutrophils, acting systemically (23).
biologic events that involve more peripheral quiet regions of            Taken in sum, the inhibition of PAF-induced bronchocon-
the lungs.                                                           striction but not of neutropenia, systemic effects, and gas ex-
    In our previous work, in both healthy subjects (3, 7, 8) and     change disturbances by ipratropium bromide, but the inhibition
in patients with mild asthma (4), we suggested that pulmonary        of all these PAF-induced changes by salbutamol in this subset
gas exchange abnormalities and the simultaneous modest in-           of asthmatic patients reinforces the view that beta-adrenergic
crease of Rrs caused by inhaled PAF were more related to             agonists may block the postcapillary venoconstriction of the
narrowing of airway caliber secondary to increased microvas-         bronchial circulation provoked by PAF. These findings en-
cular leakage than to a primary reversible constrictor effect        hance the concept that PAF can be viewed as a putative media-
(3). Platelet-activating factor, like other putative inflamma-       tor of inflammation in human airways, although a mechanistic
tory mediators in the lungs, induces increased vascular recruit-     relationship cannot be clearly established.
ment and/or vascular engorgement, vasodilation, and increased
vascular permeability, thereby causing exudation of protein-         Acknowledgment: The writers are grateful to Felip Burgos, Jaume Cardús,
rich plasma around (in mucosa, submucosa, and/or adventitia)         Conxi Gistau, Teresa Lecha, Maite Simó, and Carmen Argaña, for their out-
                                                                     standing technical support.
and within the airway lumen (17, 18). It has been suggested
that abnormal airway microvascular leakage can magnify the
bronchoconstrictor response by several mechanisms such as            References
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