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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Endothelin-1 (ET-1) has been indirectly implicated in the pathophysiology of asthma, and it is a potent bronchoconstrictor both in vitro and by inhalation in animal models in vivo. We examined the effect of inhaled ET-1 on airway tone in comparison with methacholine in eight asthmatics and five healthy volunteers in a double-blind randomized fashion. After a screening methacholine challenge each asthmatic had two ET-1 (doubling dose range, 0.96 to 15.36 nmol) and one methacholine (doubling dose range, 0.33 to 21.0 µmol) challenge, and normal subjects had a single ET-1 challenge. Inhalations were delivered using a dosimeter, and lung function measurements were made using constant-volume body plethysmography, with end points being a 35% fall in specific airway conductance (SGaw) and a 15% fall in FEV1. Samples for plasma ET-1 were taken before and after the inhalations, and pulse, blood pressure and oxygen saturation were monitored throughout the inhalations. All the asthmatic subjects displayed rapid-onset (< 5 min) dose-dependent bronchconstriction to ET-1 across the dose range used, with mean (range) ET-1 PC35SGaw values of 5.15 (1.4 to 13.9) nmol, and 4.3 (1.2 to 8.3) nmol for the two ET-1 inhalations, and 0.42 (0.2 to 0.7) µmol for methacholine. Albuterol completely and rapidly reversed ET-1-induced bronchoconstriction, and in two patients not given albuterol, bronchoconstriction lasted 60 to 90 min. No significant bronchoconstriction was observed in any of the healthy volunteers across the ET-1 dose range used (mean PC35SGaw > 15.36 nmol). Oxygen saturation did not alter in either group, and plasma ET-1 did not change after ET-1 inhalation. Noninvasive blood pressure measurements revealed a fall in systolic blood pressure in normal subjects, with no change in asthmatics. Endothelin-1 is a potent bronchoconstrictor in asthma, with a bronchoconstrictor potency around 100 times that of methacholine in asthma. Asthmatics exhibit bronchial hyperractivity to ET-1, and inhaled ET-1 can safely be given to asthmatics and normal subjects in the nebulized dose range 0.96 to 15.36 nmol.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Of the three structurally distinct 21-amino acid peptides that make up the human endothelin family (ET-1, ET-2 and ET-3) (1), the focus of interest in asthma is ET-1 since it has a number of activities that may contribute to the processes involved in the pathogenesis of asthma (2). ET-1 produces prolonged and potent contraction of animal and human airways in vitro (3) and in animal studies in vivo by aerosol administration (4). ET-1 is a mitogen for airway smooth muscle (5) and epithelial cells (6) in cell culture, and perhaps more importantly is a potent comitogen with other mediators, including epidermal growth factor (7). Application of ET-1 to the nasal mucosa results in increased nasal secretions in healthy volunteers, with a greater increase in secretions in allergic rhinitis (8), suggesting that allergic inflammation increases upper airway sensitivity to ET-1, and there is animal evidence that ET-1 may act as a proinflammatory mediator (9, 10). ET-1 is produced by human bronchial epithelial cells (11) and macrophages (12), and the bronchial epithelial cells of asthmatic patients show increased expression of ET-1 (13). Plasma levels of ET-1 have been reported to be elevated in acute exacerbation of asthma, falling with treatment of the exacerbation (14), and to correlate with clinical severity of asthma and with bronchoconstriction during a methacholine challenge test (15). Bronchoscopic studies examining bronchoalveolar lavage (BAL) fluid have shown an increase in BAL ET-1 from symptomatic and non-steroid-treated asthmatics (16), in response to segmental allergen challenge (17) and a reduction in BAL ET-1 levels after treatment of an acute exacerbation of asthma (18). Receptors for ET-1 are present on bronchial smooth muscle cells and in peripheral lung, although not at increased density in asthma (19).
We are not aware of any other studies examining the bronchoconstrictor response to aerosolised ET-1 in normal subjects or asthmatics, and the objectives of the study were to examine the effects of inhaled ET-1 on lung function in asthmatics in comparison with normal subjects and to assess the in vivo bronchoconstrictor potency of ET-1 in comparison with methacholine.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Subjects
Thirteen adult subjects were studied, subdivided into eight asthmatics
and five normal volunteers, with numbers limited by the high cost of
ET-1 (roughly $200 per inhalation). Asthmatics all had current
asthma with stable symptoms at the time of study, no history within
the preceding month of respiratory infection, antibiotics, or oral corticosteroid use, and other than house dust mite, none of the subjects
had been exposed to allergens to which they were allergic in the preceding month. Asthma was defined according to the ATS definition
(20), baseline lung function was recorded, and nonspecific bronchial
hyperresponsiveness was established using a methacholine challenge
test, with all the asthmatics subjects having a methacholine PC20 of
less than 8 mg/ml. Normal subjects had no history of breathlessness or
wheeze, normal baseline spirometry (FEV1 
70% predicted in the
absence of symptoms) and had a methacholine PC20 of greater than 16 mg/ml. The study was approved by the West Ethics Committee, West
Glasgow Hospitals University NHS Trust, and each subject gave written informed consent.
Protocol
The study was performed in randomized single-blind fashion. Asthmatic subjects attended for methacholine screening test, followed by
three visits for ET-1 (two visits) or methacholine (one visit) inhalations. Asthmatics withheld 
2-agonist therapy for 12 h prior to each
study visit. Normal subjects attended for screening methacholine challenge followed by a single visit for ET-1 inhalation. The interval between visits was not fixed, but it was generally around 1 wk for most
subjects. On the study days, blood was sampled for plasma ET-1 assay
before and after each inhalation, and oxygen saturation (SaO2) recorded
by pulse oximetry and noninvasive blood pressure were recorded at
regular intervals through the inhalations. Both ET-1 and methacholine were administered using an air-driven dosimeter (Nebicheck; PK
Morgan Ltd, Gillingam, UK), calibrated to deliver 0.006 ml/breath,
with a doubling dose range for ET-1 of 0.96 to 15.36 nmol and methacholine of 0.33 to 21.0 µmol. Dried purified ET-1 (Thistle Research,
Glasgow, UK) was reconstituted in 0.9% saline prior to nebulization,
and methacholine was prepared by sterile pharmacy in our own hospital. The nebulisate was prepared by a second operator, with both patient and principal operator blinded to the contents of the nebulizer
chamber. Measurements were made using a constant-volume body
plethysmograph (Masterlab v4.2; Erich Jaeger GmbH, Wuerzburg,
Germany) with assessment of specific airway conductance (SGaw)
and FEV1 5, 10, and 15 min after each dose of study drug. The inhalation was stopped after a 15% fall in FEV1 or after the maximal dose in
the dosing schedule, whichever came first, and on all but two occasions albuterol (2.5 mg nebulized) was given and measurements were
repeated after 10 min. On two occasions, albuterol was not given, and
measurements were continued until the SGaw had returned to within
25% of the prechallenge value to assess the duration of bronchoconstriction in these patients (both asthmatic).
Laboratory Processing and Biochemical Assays
After venepuncture, blood was centrifuged at 3,000 rpm for 10 min and the resulting supernatant was frozen and stored for ET-1 assay. After thawing, plasma samples were preextracted using C-18 columns (Waters Ltd, Watford, UK) prior to ET-1 assay by radioimmunoassay (RIA) (Nichols Institute Diagnostics Ltd., San Juan Capistrano, CA). The lower limit of detection is about 2 pg /ml in plasma, and assays were run in duplicate, with the mean value used for analysis. To ensure that ET-1 was not altered by nebulization, a sample of ET-1 was returned for ET-1 assay after nebulization, and this confirmed that there was no loss of activity of ET-1.
Data Handling and Statistical Analysis
Lung function values were calculated using the software linked to the constant-volume body plethysmograph (Erich Jaeger), and they are expressed as percent of baseline value except where stated. Statistics were performed on an Apple Macintosh desktop computer (Apple Computer Inc., Cupertino, CA) using a statistical software package (Minitab Statistical Software, Minitab Inc., State College, PA). Demographic factors and baseline and maximal fall in lung function parameters were analyzed using parametric statistics (t test) with correction for multiple comparisons, and preinhalation and postinhalation plasma ET-1 values were compared using nonparametric statistics (Mann-Whitney U test), with significance accepted at the 95% level in each case.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Patient Demographics
Comparison of demographic factors revealed that subjects in the asthmatic group were older (p < 0.05) on average than those in the normal group. SGaw and FEV1 (absolute and percent predicted) were lower in the asthmatic group than in the normal group (Table 1) and there was no difference between asthmatics' baseline values of FEV1, SGaw, or SaO2 on the 3 study days (Table 2).
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Pulse Oximetry
In both asthmatics and normal subjects, pulse oximetry was normal prior to methacholine and ET-1 inhalations, and it did not alter significantly during any of the inhalations, with a mean "fall" of less than 1% for all the inhalations (Table 2).
Pulse and Blood Pressure
There was no significant change in pulse rates for any of the inhalations, in either asthmatics or normal subjects. In the asthmatic group mean (SD) blood pressure (systolic/diastolic) was 120 (9.6)/75 (10.0) mm Hg before and 119 (8.2)/72 (9.4) mm Hg after methacholine inhalation; 121 (8.7)/80 (6.1) mm Hg before and 123 (11.8) /76 (5.9) mm Hg after for the first ET-1 inhalation; 121 (8.3)/73 (7.4) mm Hg before and 121 (9.0)/73 (6.4) mm Hg after for the second ET-1 inhalation. These represent percent changes of less than 4% in each case, and these changes were not statistically significant. In normal subjects mean (SD) blood pressure was 123 (6.8)/71 (2.8) mm Hg before and 113 (5.3)/73 (5.0) mm Hg after ET-1 inhalation, and the fall in systolic blood pressure did reach statistical significance (p = 0.03).
Plasma Endothelin-1
Normal subjects had no change in plasma ET-1 across the ET-1 inhalation: median (IQR) before and after ET-1 challenge, 2.2 (2.1 to 2.5) pg/ml and 2.0 (1.5 to 2.5) pg/ml, respectively. In asthmatic subjects there was no change in plasma ET-1 across the methacholine inhalation: median (IQR) before and after methacholine challenge, 3.3 (2.1 to 3.9) pg/ml and 3.0 (2.0 to 3.5) pg/ml, respectively, nor across either of the ET-1 inhalations: median (IQR) before and after ET-1 challenge, 3.2 (2.9 to 4.5) pg/ml and 3.8 (2.8 to 4.6) for the first ET-1 inhalation, and 3.3 (3.0 to 4.0) and 4.0 (2.9 to 4.3) for the second ET-1 inhalation. Both pre- and post-ET-1 inhalation values were higher in asthmatics than in normal subjects for both ET-1 inhalations, but this did not reach significance for the methacholine inhalation.
SGaw
Individual dose-response graphs for asthmatic subjects are presented in Figure 1, indicating that all the asthmatic subjects experienced a dose-related fall in SGaw over the dose range used, with a mean (SD) fall in SGaw of 69.7 (15.9)% for methacholine, and 63.0 (11.8)% and 60.5 (14.9)% for the two ET-1 inhalations. The mean (SD) concentration required to produce a 35% fall in SGaw (PC35SGaw) in asthmatics was 0.42 (0.18) µmol for methacholine, 5.15 (4.4) nmol for the first ET-1 inhalation, and 4.29 (2.5) nmol for the second ET-1 inhalation, suggesting that ET-1 is around 100 times more potent as a bronchoconstrictor in asthma than is methacholine on a molar basis (range, 30 to 350 times for individual patients). Treatment with albuterol (2.5 mg nebulized) completely reversed bronchoconstriction in all cases. The correlation between methacholine PC35SGaw and ET-1 PC35SGaw was not significant (in contrast to PC15FEV1 below). None of the normal subjects experienced a significant fall in SGaw: mean (SD) fall in SGaw, 9.2 (10.6)%, even at the top of the dose range (15.36 nmol) of ET-1 (Figure 2) (ET-1 PC35SGaw for normal subjects is > 15.36 nmol).
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FEV1
Individual dose response graphs for asthmatic subjects are presented in Figure 1. Although the mean (SD) fall in FEV1 was 20.1 (8.9)% for methacholine, 18.3 (6.9)% for the first ET-1 inhalation, and 16.25 (5.1)% for the second ET-1 inhalation (Table 2), and all had a dose-related fall in FEV1, two of the asthmatic patients had a fall in FEV1 of less than our target of 15% after the maximal dose of ET-1 (15.36 nmol). Values for provoking concentrations of ET-1 required to produce a 15% fall in FEV1 (PC15FEV1) are therefore calculated using geometric extrapolation of the fall at the maximal dose for these two patients (three ET-1 inhalations). Mean PC15FEV1 concentrations for the asthmatic group were 0.93 (0.66) µmol for methacholine, 10.52 (11.6) nmol for the first ET-1 inhalation, and 12.15 (8.12) nmol for the second ET-1 inhalation, again suggesting that ET-1 is roughly 100 times as potent a bronchoconstrictor in asthma as methacholine on a molar basis (range, 25 to 200 times for individual patients). The correlation between methacholine PC15FEV1 and ET-1 PC15FEV1 was strong (r = 0.912 and 0.816 for each ET-1 inhalation) and statistically significant (p = 0.002 and 0.014, respectively). None of the normal subjects experienced any significant fall in FEV1 with a mean (SD) change of 0.4 (0.9)% from baseline (Figure 2) (ET-1 PC15FEV1 for normal subjects is > 15.35 nmol).
Duration of Bronchoconstriction
Duration of bronchoconstriction was not examined as a formal part of the study protocol, but in two asthmatic patients, albuterol was not given at the end of inhalation of ET-1 on their final visit, and these patients' serial lung function measurements were made until the SGaw had returned to within 25% of baseline values. In one patient this took 60 min, and in the other, 90 min.
Repeatability
Repeatability of the two ET-1 inhalations was assessed using the method described by Bland and Altman (21) to establish a repeatability coefficient, by comparing the standard deviations of the differences in PC35SGaw values for each asthmatic patient for the two ET-1 inhalations. This gives a repeatability coefficient (2 × SD of the differences) of 8.47 nmol for a PC35SGaw evaluation, with seven of eight values lying within this range (the value outwith this range was a difference of 8.93 nmol), suggesting reasonable repeatability for PC35SGaw estimation.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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We have demonstrated for the first time that endothelin-1 (ET-1) is a highly potent bronchoconstrictor in asthma, with a relative potency to methacholine of about 100 times on a molar basis, and that asthmatics exhibit bronchial hyperreactivity to ET-1 compared with normal subjects. Relatively rapid onset (< 5 min) bronchoconstriction occurs in a dose-dependent fashion, and we conclude that ET-1 can be safely given by inhalation to asthmatics and normal subjects as a bronchial challenge test in a dose range of 0.96 to 15.36 nmol. We observed no change in blood pressure, oxygen saturation, or plasma ET-1 levels related to the inhalation of ET-1. Albuterol completely reversed ET-1-induced bronchoconstriction, and the duration of bronchoconstriction was at least 60 and 90 min in the two patients formally assessed.
We observed bronchoconstriction within 5 min of ET-1 inhalation, which is in keeping with animal studies using aerosolized ET-1 where the maximal response was reached in around 4 to 5 min (4), and Henry and coworkers (22) observed a similar time to reach maximal contraction (5 to 10 min) in human isolated bronchi. Henry and coworkers expressed the contractile potency of ET-1 as the concentration needed to produce a contraction 30% of the maximal contractile response to 10 µM carbachol (excitatory concentration, EC30), with a value of 35 nM. Although it is difficult to directly relate that figure to a dose given in vivo, allowing for the increased sensitivity we have observed in asthmatics, it is of similar order of magnitude and relative potency to methacholine as we found in this study expressed as ET-1 provoking concentrations for SGaw and FEV1. The dose range used in this study was based on in vitro studies of the bronchoconstrictor response in human airway (23), along with pilot work on healthy volunteers starting with inhalations of significantly lower concentrations of ET-1 to establish overall safety of the technique. The nature of nebulization even with a dosimeter means that although it is possible to be reasonably accurate in terms of the dose nebulized, the effective dose reaching the lungs is much harder to assess, but it is probably of the order of 20 to 30% of the doses stated.
We found increased plasma ET-1 in asthmatics compared with that in normal subjects both before and after the 2 ET-1 inhalations (although with no change across the inhalations), but no significant difference on the day of the methacholine inhalation. This finding does not reflect our own previous experience with plasma levels (unpublished data) where we found no difference between subjects with mild asthma and normal subjects, and although we are aware of one study that correlates plasma ET-1 with lung function (15), we presume, pending further data, that this finding is a consequence of the small numbers in each group. The lack of change in blood pressure during ET-1 inhalation is in keeping with animal studies using aerosolized ET-1 (4).
The contractile activity of ET-1 on bronchial smooth muscle has been assessed in animal models, and in human tissue in
vitro. Aerosol administration of ET-1 in animal studies produces a dose-dependent bronchoconstriction, with no blood
pressure response (4), no increase in bronchial hyperreactivity
or histamine response (24), and no inflammatory reaction
(25), and there is evidence from animal studies that the responses to intra-arterial and aerosolized ET-1 are mediated by
different mechanisms (26). In vitro studies have confirmed
that bronchoconstrictor activity of ET-1 in human bronchi
(27), although in contrast to our findings in vivo, Goldie and
coworkers (3) found no difference between asthmatic and
nonasthmatic bronchi in sensitivity to ET-1 in vitro, and in the
same study they demonstrated no increase in ET-1 binding sites in asthmatic bronchi (nor in asthmatic peripheral lung
(19) in a study from the same group), suggesting that the bronchial hyperractivity to ET-1 that we observed does not depend
simply on increased ET-1 receptor numbers in asthma. In human isolated bronchi, ET-1 exerts its contractile effect mainly
through the action of the ETB receptor subtype (28), which is
the most numerous receptor in this tissue, although, interestingly, bronchial smooth muscle from asthmatic lung appears
to be less sensitive to the contractile effects of a specific ETB
receptor agonist, sarafotoxin S6c (29), presumably because of
a decrease in receptor sensitivity. The above data, with our
finding that asthmatics exhibit bronchial hyperreactivity to
ET-1 in vivo, suggests that factors other than receptor numbers and sensitivity contribute to this increased sensitivity to
ET-1 in asthma since it would not be predicted from the in
vitro receptor data. Epithelial disruption is a feature of the inflammation associated with asthma (30), and it has been demonstrated that epithelial removal significantly enhances the
contractile activity of ET-1 in the human isolated bronchus (31), raising the possibility that epithelial disruption contributes to increased contractile activity of ET-1 in asthma. It has
also been demonstrated in vitro that ET-1 may interact with
other mediators implicated in asthma, with potentiation of its
contractile activity, including prostaglandins PGD2 and PGF2
,
leukotriene D4 (32), and angiotensin II (33), but other than
the findings of increased nasal mucosal sensitivity to ET-1 in
allergic rhinitis (8) and a rise in endothelin-like immunoreactivity 24 h after allergen challenge in sensitized guinea-pig airways (34), there are no direct data on the contribution of airway inflammation to ET-1 activity. The absence of response to
inhaled ET-1 in normal subjects is striking and supports the
observation that an intact airway epithelium modulates the response of airway smooth muscle to ET-1 (35). Although the
mechanism for this is not known, an intact epithelium in normal subjects might form a physical barrier to ET-1 coming
into contact with submucosal target cells or increase clearance
and metabolism of ET-1, either by binding and internalization
of ET-1 by ETB receptors (36) or by enzymatic degradation.
There is also evidence in nonasthmatic human tissue that ET-1
can act on ETA receptors in bronchial epithelium causing release of relaxant factors, including nitric oxide (37), which could
attenuate the bronchoconstrictor effects of ET-1 in normal airways.
There is debate about the mechanism of action of ET-1 in
the airways, with animal studies suggesting that contractile activity is at least in part mediated by arachidonic acid metabolites (in particular thromboxanes) (38), leukotrienes, and histamine (39), but this has not been confirmed by studies using
human bronchi (23) where ET-1 appears to act directly on
smooth muscle without the involvement of acetylcholine, leukotrienes, histamine, or platelet-activating factor (40). Although this study was not designed to examine the mechanism
of action of ET-1, the strong correlation that we observed between methacholine reactivity and ET-1 reactivity (at least for
FEV1 response) lends indirect support to the suggestion that
ET-1, like methacholine, exerts its bronchoconstrictor effect
directly on bronchial smooth muscle rather than through a
second mediator. This is not conclusive, however, and ET-1 is known to have other effects that could lead to muscular or
nonmuscular bronchial narrowing. ET-1 acts on glandular ET
receptors in human nasal mucosa, inducing lactoferrin and
mucous glycoprotein release (41), induces cytokine production (GM-CSF, IL-6, and IL-8) in human bronchial epithelial
cell culture (42), and potently stimulates release of TNF-
, IL-1, and IL-6 from monocytes and monocyte-derived macrophages (43), all of which could contribute to nonmuscular airway obstruction. In addition, ETB receptor activation has
been shown to potentiate cholinergic nerve-mediated contraction in human bronchial preparations (44), suggesting that
ET-1 might exert an additional neurally mediated bronchoconstrictor effect.
Further work is needed to clarify the mechanism of action of ET-1 in human airways, and in particular to examine the influence that the specific bronchial microenvironment associated with asthmatic airway inflammation might have on the increased sensitivity to ET-1 that we have observed in asthma. These data support a role for ET-1 in the pathophysiology of asthma and provide a potential means of further exploring this role through the use of ET-1 in bronchial challenge testing.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. George W. Chalmers, Dept. of Respiratory Medicine, West Glasgow Hospitals University NHS Trust, Glasgow G12 OYN, UK.
(Received in original form February 18, 1997 and in revised form April 4, 1997).
Acknowledgments: The writers wish to acknowledge the help of Dr. J. J. Morton of the University of Glasgow Department of Medicine who performed the endothelin assays.
Supported by the National Asthma Campaign, United Kingdom.
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References |
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REFERENCES
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