 2-Receptor Dysfunction in Isolated Human Bronchi
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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Antigen challenge causes 
2-adrenoceptor dysfunction in sensitized human bronchi (Am. J. Respir.
Crit. Care Med. 1997;155:1230-1234). This study investigated whether the dysfunction can be prevented by anti-inflammatory agents. Human bronchial rings (2 to 4 mm) from surgery were passively
sensitized to house dust mite and challenged (1) with allergen only, (2) with allergen plus indomethacin (10
5 M), (3) with allergen plus nedocromil sodium (107 M to 105 M), (4) with allergen plus the H1-receptor antagonist cetirizine (107 M to 105 M), and (5) with allergen plus the peptido-leukotriene receptor antagonist iralukast (107 M to 105 M). Rings were first contracted with
106 M carbachol and then relaxed with salbutamol (109 M to 104 M). The concentration-relaxation curve to salbutamol was shifted significantly to the right in the rings challenged with allergen only compared with control rings. In the rings challenged with allergen plus nedocromil sodium
(106 M and 105 M) or iralukast (106 M and 105 M) the concentration-relaxation curves to salbutamol were significantly shifted to the left compared with rings challenged in saline alone, suggesting a protective effect against 2-adrenoceptor dysfunction. Neither allergen plus cetirizine nor
allergen plus indomethacin shifted significantly the concentration-relaxation curves to salbutamol compared with rings challenged in saline alone. We conclude that the release of peptido-leukotrienes
may play a significant role in causing the allergen-induced 2-receptor dysfunction in passively sensitized human bronchi.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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-Adrenoceptor desensitization can be induced in airway
smooth muscle (1, 2) by exposure to -agonists (homologous
desensitization) (3) or inflammatory mediators (4). In allergic
asthma, several products are released from resident and circulating inflammatory cells upon exposure to allergen, which
may contribute to the development of tolerance to -agonists.
In vitro, 2-adrenoceptor dysfunction occurs in passively sensitized human bronchi after an allergen challenge (5), suggesting that one or more mediators released from resident cells
(most likely mast cells) cause 2-adrenoceptor desensitization.
Mast cell mediators involved in the allergic response include
histamine, leukotrienes, and prostaglandin D2.
This study was undertaken to investigate whether the allergen-induced 2-adrenoceptor dysfunction of passively sensitized human bronchi can be prevented by anti-inflammatory
agents. The relaxant effect of salbutamol was studied in passively sensitized human bronchi challenged with allergen in
the absence or presence of (1) the cell membrane stabilizer
nedocromil sodium, (2) the peptido-leukotriene receptor antagonist iralukast (CGP45715A), (3) the H1-receptor antagonist cetirizine, and (4) the cyclooxygenase inhibitor indomethacin.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Tissue Preparation
Bronchi were obtained from 18 nonasthmatic patients (14 men, 4 women) age 45 to 70 yr, undergoing surgery for lung cancer. No patient had received 2-agonists, theophylline, or anticholinergic drugs
in the 24 h before or during operation. None of the patients was sensitized to Dermatophagoides pteronyssinus or farinae, as determined by
prick test (Lofarma, Milan, Italy).
Surgical specimens were immersed into aerated (95% O2 and 5% CO2) physiologic salt solution (PSS) of the following composition (mM): NaCl 110.5; KCl l3.4; CaCl2 2.4; MgSO4 0.8; KH2PO4 1.2; NaHCO3 25.7; and dextrose 5.6. Rings from bronchi (internal diameter 2 to 4 mm, length 4 to 5 mm) remote from the site of malignancy were prepared by careful dissection and removal of parenchymal tissue. Attention was paid to avoid epithelial damage.
Passive sensitization. Bronchial rings were passively sensitized overnight (18 h) by incubation with 1 ml serum diluted with 9 ml of PSS from three Dermatophagoides-sensitized donors. The serum concentration of specific IgE to Dermatophagoides of the sensitized donors was > 17.5 Phadebas RAST Units (PRU)/ml (fourth RAST class; Pharmacia, Uppsala, Sweden), and the total serum IgE concentration was 337 ± 89 international units (IU)/ml. Bronchial rings were maintained at room temperature and continuously gassed with 95% O2 and 5% CO2. One ring from each patient (control ring) was sham-incubated with 1 ml of serum from nonatopic donors (total serum IgE concentration < 20 IU/ml and negative RAST for Dermatophagoides) diluted in 9 ml of PSS.
Treatments. After the overnight incubation, rings were washed
with PSS for 15 min. Three sensitized rings from six patients each
were incubated for 30 min with 107 M, 106 M, or 105 M nedocromil
sodium, iralukast, or cetirizine. One ring from each bronchus used for
the nedocromil study was incubated with 105 M indomethacin. Control rings and two sensitized rings from each patient were incubated
with PSS without any anti-inflammatory drug.
Allergen challenge. All rings treated with anti-inflammatory drugs (hereafter referred to as treated rings) and one untreated sensitized ring (hereafter referred to as challenged rings) from each patient were challenged by adding 200 arbitrary units (AU)/ml of Dermatophagoides mix (Lofarma, Milan, Italy) to 5 ml of aerated PSS (37° C) for 60 min. The remaining untreated sensitized (hereafter referred to as sensitized rings) and control rings were sham-challenged with PSS for 60 min at 37° C.
Procedures
Bronchial rings (control, sensitized, challenged, and treated rings) were suspended by two stirrups in 25-ml tissue baths containing aerated PSS (37° C). The lower stirrup was connected by a silk string to a stationary hook at the bottom of the tissue bath while the other stirrup was connected by a silk string to a force transducer (Model FT03D; Grass Medical Instruments, Quincy, MA) mounted on a micromanipulator. Isometric force was continuously recorded on a Gould TA 400 strip chart recorder. The rings were allowed to equilibrate in the baths for 2 h and washed with PSS every 15 min. During this time they were progressively stretched to a resting force of 1 × g, which had been determined to correspond to the optimal length in human bronchi of this size. The length was not changed throughout the study.
Concentration-relaxation curve to salbutamol. Rings were precontracted with carbachol 106 M. When the contraction was stable the
rings were incubated for 10 min each with cumulatively increasing
concentrations of salbutamol (109 M to 104 M with half-log increments).
Assessment of sensitization. One sensitized ring from each patient was not used for the determination of the concentration-relaxation curve to salbutamol. Evidence of sensitization was obtained by exposing these rings to 1,000 AU of Dermatophagoides mix in the 25 ml of the tissue bath for 1 h and recording the contractile response. In 16 of 18 patients the control rings were challenged with allergen at the end of study to rule out the presence of natural sensitization.
Concentration-response curve to carbachol. To rule out that the
contraction induced by 106 M was affected by treatment, four sensitized rings from three additional patients each were incubated with
105 M nedocromil sodium, 105 M iralukast, 105 M cetirizine, or
PSS. They were challenged with Dermatophagoides mix, transferred
to the tissue baths and washed for 2 h every 15 min. The concentration-response curves to carbachol (109 M to 104 M with half-log increments) were then determined.
Data Analysis
The active force was measured from the resting force prior to the carbachol-induced contraction.
The concentrations of salbutamol inhibiting 50% of active force (IC50) were calculated by linear interpolation between two adjacent points of the concentration-relaxation curves. Two-factor repeated-measure analysis of variance (ANOVA) with Newman-Keuls post hoc test was used for statistical analysis. Differences were considered statistically significant at p < 0.05. Data are presented as mean ± SD.
Drugs
Salbutamol free base, carbachol (carbamylcholine chloride), and indomethacin were purchased from Sigma Chemical Company (Milan, Italy). Dermatophagoides pteronyssinus and farinae mix were purchased from Laboratorio Farmaceutico Lofarma (Milan, Italy).
Iralukast was generously provided by Ciba-Geigy Ltd. (Basel, Switzerland), nedocromil sodium by Rhône-Poulenc Rorer SpA (Origgio,
Italy), and cetirizine dihydrochloride by UCB (Braine-l'Alleud, Belgium). A stock solution of 104 M indomethacin was prepared with
100% ethanol and diluted with distilled water; other drugs were dissolved in distilled water.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The mean weight of the 114 bronchial rings (rings used for concentration-response curves to carbachol and for allergen-induced contraction not included) was 100 ± 42 mg and the mean resting force, 1 ± 0.2 g. Mean weights and resting forces of the control, sensitized, challenged, and treated rings were not significantly different within (p = 0.3) or between (p = 0.4) studies.
Response to Carbachol
The concentration-response curves to carbachol of treated
and challenged rings did not differ significantly (p > 0.7). The maximal response to carbachol 104 M was (force/wet tissue
weight) 29 ± 10 g/g for challenged rings, 30 ± 7 g/g for
nedocromil sodium-treated rings, 33 ± 6 g/g for iralukast-treated rings, and 28 ± 7 g/g for cetirizine-treated rings. The
response to carbachol 106 M (percent of maximal response)
was 51 ± 13% for challenged rings, 50 ± 18% for nedocromil
sodium-treated rings, 55 ± 5% for iralukast-treated rings, and
52 ± 1% for cetirizine-treated rings.
Effect of Passive Sensitization and Challenge
The salbutamol concentration inhibiting 50% of active force (IC50) was in all experimental groups larger (p < 0.05) in the challenged than in the sensitized and in the control rings (Table 1).
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LOG M) INHIBITING 50% OF ACTIVE FORCE (IC50)*Effect of Nedocromil Sodium
The contraction induced by carbachol 106 M was not significantly different between control (15 ± 7 g/g), sensitized (17 ± 8 g/g), challenged (16 ± 9 g/g), and treated rings (17 ± 7 g/g at nedocromil sodium 107 M, 18 ± 7 g/g at nedocromil sodium
106 M, and 17 ± 9 g/g at nedocromil sodium 105 M). The
concentration-relaxation curves to salbutamol of rings treated
with nedocromil sodium 106 M and 105 M were significantly
(p < 0.03) shifted to the left as compared with those of challenged rings, suggesting a protective effect against 2-adrenoceptor dysfunction. The curves were not significantly different
from those of control (p > 0.4) and sensitized (p > 0.5) rings
(Table 1 and Figure 1).
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Effect of Iralukast
The contraction induced by carbachol 106 M was not significantly different between control (14 ± 8 g/g), sensitized (15 ± 6 g/g), challenged (14 ± 7 g/g), and treated rings (16 ± 8 g/g at iralukast 107 M, 17 ± 7 g/g at iralukast 106 M, and 18 ± 4 g/g
at iralukast 105 M). The concentration-relaxation curves to
salbutamol of rings treated with iralukast 106 M and 105 M
were significantly (p < 0.02) shifted to the left as compared with those of challenged rings, but not significantly different from those of control (p > 0.5) and sensitized (p > 0.6) rings (Table 1 and Figure 2).
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Effect of Cetirizine
The contraction induced by carbachol 106 M was not significantly different between control (15 ± 4 g/g), sensitized (19 ± 6 g/g), challenged (16 ± 4 g/g), and treated rings (16 ± 3 g/g at cetirizine 107 M, 18 ± 4 g/g at cetirizine 106 M, and 17 ± 5 g/g
at cetirizine 105 M). The concentration-relaxation curves to
salbutamol of cetirizine-treated rings were not significantly
different (p > 0.8) from those of challenged rings but significantly shifted to the right compared with those of control (p < 0.02) and sensitized (p < 0.04) rings (Table 1 and Figure 3).
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Effect of Indomethacin
The contraction induced by carbachol 106 M was not significantly different between control (15 ± 7 g/g), sensitized (17 ± 8 g/g), challenged (16 ± 9 g/g), and treated (18 ± 8 g/g) rings. The concentration-relaxation curves to salbutamol of indomethacin-treated rings were not significantly different from
those of challenged (p > 0.3), control (p > 0.2), or sensitized
(p > 0.2) rings (Table 1 and Figure 4).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The main findings of the present study are that treatment with
the cell membrane stabilizer nedocromil sodium or the peptido-leukotriene receptor antagonist iralukast prevented the
allergen-induced 2-receptor dysfunction in passively sensitized human bronchi.
Comments on Methodology
In a previous study using human bronchial rings passively sensitized with near-normal total IgE concentrations, we showed that an allergen challenge followed by a 2-h washout did not
alter the response to carbachol (5). In the present study we
ruled out that incubation with 105 M nedocromil sodium,
105 M iralukast, or 105 M cetirizine altered the contractile
response of challenged rings to carbachol. These findings suggest that the force-generating capacity of the airway smooth
muscle was similar under all experimental conditions. This is
a crucial point for interpreting the results of the present study
in terms of 2-adrenoceptor function, as passive sensitization
with sera containing high total IgE concentrations increases
the velocity and magnitude of airway smooth muscle shortening and also the isometric force (6, 7) and may induce myogenic contractile response (8).
We ruled out that nedocromil sodium and iralukast have a
direct effect on 2-adrenoceptors. Concentration-relaxation
curves to salbutamol in control and sensitized unchallenged
rings from three additional patients were not altered 2 h after
incubation for 30 min with nedocromil sodium 105 M or
iralukast 105 M.
In the previous study (5) we also showed that the relaxant effect of theophylline was maintained after allergen challenge of passively sensitized human bronchial rings, suggesting that the relaxing properties of the contractile elements were not altered.
Intact bronchial rings were used. It is therefore impossible
to distinguish between desensitization of 2-adrenoceptors on different cells (airway smooth muscle, mast cells, epithelial cells, vascular cells, and nerves).
Effect of Nedocromil Sodium
Incubation with nedocromil sodium during allergen challenge
prevented 2-adrenoceptor dysfunction in a concentration-
dependent manner. The most documented effect of nedocromil sodium is the stabilization of methachromatic cell membrane (9, 10). This is expected to inhibit mediator release and,
in turn, the contractile response to allergen. In two separate
experiments, the contractile response to allergen was reduced
by nedocromil sodium in a concentration-dependent manner
(Figure 5). It is therefore possible that some of the inflammatory mediators responsible for the contractile response to allergen are also involved in the development of 2-adrenoceptor dysfunction.
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Effect of Iralukast
Leukotrienes are produced by bronchial mast cells and epithelial cells upon IgE-mediated activation of 5-lipoxygenase-activating protein (FLAP) and 5-lipoxygenase enzyme (11, 12).
Experiments using human tissue suggest that leukotrienes are
the major mechanisms responsible for the airway response to
allergen (13). In guinea pig leukotrienes induced -adrenoceptor dysfunction (4). In the present study, incubation of sensitized human bronchi with the specific leukotriene D4-receptor antagonist iralukast during allergen challenge prevented
2-adrenoceptor dysfunction in a concentration-dependent
manner. In a separate experiment, iralukast also inhibited the
contractile response to allergen in a concentration-dependent manner (Figure 5). This suggests that leukotrienes are involved in both the contractile response and the 2-adrenoceptor dysfunction induced by allergen challenge in vitro.
The results of the present study do not allow identification
of the mechanism by which leukotrienes may cause -adrenoceptor dysfunction. In dogs, both leukotriene-C4 and leukotriene-D4 potentiate the excitatory junction potentials evoked
by electric field stimulation, suggesting a possible enhancement of acetylcholine release (14). In guinea pig, leukotrienes
may cause an increase of sensory nerve mediator release by a
prejunctional mechanism (15). The present study was not designed to evaluate prejunctional mechanisms, therefore any
effect on neurally mediated contraction cannot be excluded. Other mechanisms by which leukotrienes may impair the relaxant effect of a 2-agonist are functional antagonism (16)
and 2-adrenoceptor desensitization (4, 17). The latter could
be the result of leukotriene-induced activation of protein kinase
C (18) and -adrenoceptor phosphorylation (19).
Effect of Cetirizine
Histamine is released from methachromatic cells of the lung
during an allergic reaction (20). In the present study, the potent and selective H1-receptor antagonist cetirizine did not prevent the allergen-induced 2-adrenoceptor dysfunction and
also failed to protect against allergen-induced contraction (Figure 5). Reasons for this could be that histamine is not released
in sufficiently large amounts or the number of H1-receptors is
small in these bronchi. However, allergen challenge of passively sensitized human bronchi caused a measurable release
of histamine (20). It is possible that histamine is rapidly inactivated by histamine N-methyltransferase present in airway epithelial cells (21). Alternatively, the effects of histamine in our
model may be in part independent of H1-receptor activation,
which would make cetirizine ineffective.
Effect of Indomethacin
Prostaglandin (PG) E2 is produced in the epithelial cells upon
activation of the inducible isoenzyme cyclooxygenase (COX)-2 (22) and in the smooth muscle cells upon activation of the constitutive isoenzyme COX-1 (23). PGD2 is produced in mast
cells (24). PGE2 antagonizes airway smooth muscle contraction (25) and contributes to -adrenoceptor desensitization
(26). PGD2 induces airway smooth muscle contraction (27),
but its effects on 2-adrenoceptors are unknown.
Indomethacin is a nonselective blocker of both COX-1 and
COX-2. Depending on the relative production of PGs with
different activities the net effect of indomethacin may vary.
Indeed, in the present study, indomethacin had inconsistent
effects on both allergen-induced contraction (Figure 5) and
the associated 2-adrenoceptor dysfunction.
Conclusions
This study suggests that the release of leukotrienes is involved
in the development of 2-adrenoceptor dysfunction after allergen challenge of passively sensitized human bronchi. Although these data cannot be extrapolated to bronchial asthma,
they suggest that anti-inflammatory treatment with the mast
cell stabilizer nedocromil sodium or a leukotriene-receptor
antagonist may prevent 2-adrenoceptor dysfunction after exposure to allergen.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Vito Brusasco, M.D., DISM, Facoltà di Medicina e Chirurgia, Largo R. Benzi 10, 16132, Genova, Italy.
(Received in original form January 27, 1998 and in revised form July 27, 1998).
Dr. P. Song was supported by Rhône-Poulenc Rorer.Acknowledgments: The authors thank Dr. Maurizio Chiaramondia and Mr. Mauro Zampini from the Department of Pathology of the S. Martino Hospital and also Prof. Roberto Fiocca and Mr. Maurizio Boggio from the Department of Pathology of the University of Genova for the valuable assistance in selecting and providing tissues.
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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