 2-agonists on Histamine-induced Airway
Microvascular Leakage in Ozone-exposed Guinea Pigs
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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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2-adrenergic agonists exhibit antipermeability effects in the airways. However, it is not known
whether 2-agonists have this beneficial effect in airway mucosa that is already inflamed. We evaluated the effects of two inhaled 2-agonists, salbutamol and formoterol, on the histamine-induced
bronchoconstriction and plasma extravasation in the airways of guinea pigs with or without ozone
exposure. Total pulmonary resistance (RL) was measured before and after histamine inhalation in
anesthetized animals that were pretreated with inhaled salbutamol, formoterol, or saline. Plasma extravasation in the airways was measured using Evans blue dye. In the control animals not exposed to
ozone, salbutamol and formoterol each significantly reduced both the histamine-induced bronchoconstriction and the plasma extravasation in the trachea and main bronchi. In the ozone-exposed animals, the increase in RL after histamine was greater than that in control animals. Salbutamol and formoterol each significantly reduced histamine-induced bronchoconstriction, even in the ozone-exposed
animals. Salbutamol did not affect the histamine-induced plasma extravasation, whereas formoterol
reduced the plasma extravasation in the main bronchi, but not in the trachea, of the animals exposed
to ozone. These results suggest that the anti-inflammatory properties of formoterol in inflamed airways may contribute to the beneficial effects in the treatment of airway inflammation.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Microvascular leakage in the airways is an important component of airway inflammation and may contribute to the pathogenesis of asthma (1, 2). Thus, microvascular leakage and subsequent airway edema are thought to be involved in airflow obstruction and bronchial hyperresponsiveness. Substances that reduce plasma extravasation could be beneficial in the treatment of asthma.
2-adrenergic agonists, which are the most effective bronchodilators in current clinical use, exhibit antipermeability effects in animal models of acute airway inflammation (3).
Their administration both intravenously and by inhalation has
been shown to reduce the microvascular leakage in the airways induced by various mediators such as histamine, bradykinin, platelet-activating factor, and vagal stimulation.
It is not known, however, whether 2-agonists exhibit antipermeability effects even in the inflamed airway mucosa, such
as in asthma. Recent clinical studies report that the chronic,
regular use of 2-agonists alone does not improve the airway
hyperresponsiveness of asthmatic subjects (9, 10), which suggests that 2-agonists might not affect airway inflammation in
asthmatics. In some animal studies, intravenous administration of these drugs has failed to show an inhibitory effect on
plasma extravasation (6, 11, 12). Because 2-agonists dilate
the blood vessels and increase blood flow in the bronchial circulation (13), they might exacerbate airway microvascular
leakage by increasing blood flow to leaky vessels in the inflamed airways. In the present study, we sought to determine
whether 2-agonists can inhibit the microvascular leakage induced by further inflammatory stimulation in the already inflamed airways.
We addressed this question using a model of ozone-induced
airway inflammation. Ozone inhalation reportedly increases
airway permeability, induces neutrophil influx into the airways,
and induces bronchial hyperresponsiveness both in animals
(14) and in humans (17). We evaluated the effects of
inhaled salbutamol, an intermediate-acting 2-agonist, and of
formoterol, a long-acting 2-agonist, on histamine-induced bronchoconstriction and airway plasma extravasation in guinea
pigs with or without exposure to ozone.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal Preparation
Thirty male Hartley strain guinea pigs (450 to 550 g) were used in this study. On the day of the experiment, the animals were exposed to ozone or to dry air for 2 h under spontaneous breathing. Then they were anesthetized with pentobarbital sodium (50 mg/kg, intraperitoneally) 2 h after the beginning of ozone exposure, and the larynx and upper trachea were exposed. The trachea was incised immediately below the larynx, and a cannula was inserted 5 mm into the trachea. The animals were then mechanically ventilated with a respirator (Model 680; Harvard Apparatus, South Natick, MA) at a constant tidal volume of 7 ml/kg and a rate of 60 breaths/min. A catheter was introduced into a jugular vein to administer drugs. Another catheter was inserted into a carotid artery, through which blood pressure was measured by an electric manometer (LPU-01; Nihon Kohden, Tokyo, Japan).
Measurement of Airway Responses
The animals were placed supine in a body plethysmograph. Plethysmograph airflow was measured with a Fleisch pneumotachograph (TV-132T; Nihon Kohden) and a differential pressure transducer (TP-602T; Nihon Kohden). To evaluate pleural pressure, a fluid-filled catheter was introduced into the esophagus so that the maximal amplitude of pressure was obtained. Transpulmonary pressure was estimated from the difference between pleural and airway opening pressure, as measured by a differential pressure transducer (TP-603T; Nihon Kohden). Total pulmonary resistance (RL) was calculated from the transpulmonary pressure and plethysmograph airflow (20). The airway responses to histamine were assessed by RL changes.
Aerosols of salbutamol, formoterol, and histamine were generated by ultrasonic nebulizer (TUR-3200; Nihon Kohden) placed in line with the respirator. The output from the nebulizer at the port of the tracheal cannula, measured with saline in the nebulizer (at the tidal volume of 7 ml/kg and a rate of 60 breaths/min), was 20 µl/min. We used saline as the diluent for salbutamol, formoterol, and histamine.
Study Design
Guinea pigs were divided into six groups: vehicle (saline) treatment in dry air-exposed animals, the control group; salbutamol treatment in dry air-exposed animals; formoterol treatment in dry air-exposed animals; vehicle treatment in ozone-exposed animals; salbutamol treatment in ozone-exposed animals; and formoterol treatment in ozone-exposed animals. Animals in the ozone-exposed groups inhaled 3.0 ± 0.1 ppm (mean ± SD) of ozone for 2 h while awake and spontaneously breathing in a 2.4-liter exposure chamber. Ozone was generated by passing 100% oxygen through an ozonator (Model 0-1-2; Nihon Ozone, Tokyo, Japan) regulated by a variable-voltage supply. The concentration of ozone in the chamber was continuously monitored by an ultraviolet analyzer (Model 1500; Dasibi, Glendale, CA). We have demonstrated with this model that ozone exposure causes neutrophil influx into the airways, bronchial wall edema, and an increase in bronchial responsiveness to histamine in guinea pigs (21). Both RL and airway plasma extravasation were measured after histamine inhalation in anesthetized guinea pigs.
Baseline RL was measured 10 min after connection to the respirator. Then the animals were given nebulized salbutamol (5 mg/ml, 60 breaths = 100 µg; 50 mg/ml, 60 breaths = 1,000 µg), formoterol (0.5 mg/ml, 60 breaths = 10 µg), or saline (60 breaths) approximately 2.5 h after the beginning of ozone exposure, and RL was monitored. After 15 min, Evans blue dye (20 mg/kg) was administered intravenously. One minute later, histamine solution (0.6 mg/ml) or 0.9% NaCl was given by nebulizer for 30 breaths. The RL and arterial blood pressure were recorded continuously for 5 min, after which the animals were disconnected from the respirator. The plasma extravasation was then measured. The thorax was opened approximately 3 h after the beginning of ozone exposure, and a cannula was inserted into the ascending aorta through the left ventricle. The animals were perfused with 500 ml of saline at a pressure of 120 mm Hg to remove intravascular dye from the bronchial circulation. The caudal 30 mm of the trachea and the main bronchi were dissected.
We chose inhalation of 0.6 mg/ml of histamine solution for 30 breaths because this caused an almost two-fold increase in RL from
baseline values in preliminary dose-ranging studies in dry air-exposed
animals. As a result of dose-ranging studies on 2-agonist pretreatment,
we chose 5 mg/ml of salbutamol solution or 0.5 mg/ml of formoterol solution for 60 breaths, as these amounts completely inhibited the bronchoconstriction induced by histamine (0.6 mg/ml, 30 breaths).
Measurement of Plasma Extravasation
Because Evans blue binds to serum albumin when injected intravenously, spectrophotometric measurement of the quantity of dye extractable from airway tissue after the elimination of intravascular dye has been used as an index of increased microvascular leakage (22).
All tissues were weighed wet and incubated in 1 ml of formamide at 37° C for 18 h. The Evans blue dye concentration in the formamide extracts was measured by light absorbance at 620 nm using a spectrophotometer (Model UV-2200A; Shimadzu Scientific Instruments, Tokyo, Japan). The concentration was calculated from a standard curve of dye concentrations in the range of 0.1-10 µg/ml. The amount of dye extravasated in the tissues was expressed as ng/mg of wet weight.
Reagents
The following drugs and chemicals were used: pentobarbital sodium (Abbott Laboratories, North Chicago, IL), histamine diphosphate, Evans blue dye, and formamide (Sigma Chemical Co., St. Louis, MO). Salbutamol sulphate was a gift from Nippon Glaxo Ltd., Tokyo, Japan. Formoterol fumarate was a gift from Schering-Plough Ltd., Tokyo, Japan.
Statistical Analysis
Data are presented as means ± SEM. The time-dependent effects of salbutamol and of formoterol on the bronchoconstriction induced by histamine were assessed by multiple linear regression. The effects of salbutamol and formoterol on histamine-induced plasma extravasation in the airways were compared by analysis of variance (ANOVA), and the significance of differences between values was assessed with the Bonferroni correction for multiple comparisons. p Values less than 0.05 were considered to indicate statistical significance.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In dry air-exposed guinea pigs, the histamine inhalation significantly increased RL, with maximal responses observed within 1 min after the end of inhalation. Pretreatment with inhaled salbutamol or formoterol significantly reduced the increase in RL induced by histamine (Figure 1, upper panels).
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Histamine inhalation also induced extravasation of Evans blue dye in both the trachea and main bronchi. Pretreatment with inhaled salbutamol or formoterol significantly reduced the extravasation of dye in both the trachea and main bronchi (Figure 2, left panels).
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The increase in RL after histamine inhalation in the ozone-exposed animals was greater than that in control animals. The inhaled salbutamol and formoterol each significantly reduced the increase in RL induced by histamine in the ozone-exposed animals (Figure 1, lower panels). The increase in RL induced by histamine after salbutamol pretreatment did not differ from the effects seen after formoterol pretreatment (p > 0.05).
In ozone-exposed guinea pigs, pretreatment with inhaled salbutamol (5 mg/ml) did not change the extravasation of dye induced by histamine in either the trachea or main bronchi. Furthermore, a larger dose of salbutamol (50 mg/ml) also did not change the extravasation of dye induced by histamine in ozone-exposed animals. However, pretreatment with inhaled formoterol significantly reduced the extravasation of dye in the main bronchi, but the effect was not significant in the trachea (Figure 2, right panels).
Ozone exposure slightly increased the baseline (without histamine inhalation) extravasation of dye both in the trachea and in main bronchi as shown in Figure 2 (p < 0.05). Neither inhaled salbutamol nor formoterol reversed the increase in baseline extravasation of dye after ozone. In ozone-exposed animals, baseline Evans blue contents after saline inhalation, salbutamol inhalation, and formoterol inhalation were 21.9 ± 2.9, 17.9 ± 3.5, and 19.1 ± 2.8 ng/mg tissue, respectively in the trachea, and were 22.0 ± 3.1, 23.6 ± 2.1, and 23.5 ± 8.2 ng/mg tissue, respectively in the main bronchi (n = 4 or 5). There were no significant differences in baseline RL or blood pressure before pretreatment among the study groups. Both in dry air-exposed animals and in ozone-exposed animals, the inhalation of salbutamol or formoterol caused no significant changes from the baseline RL (Table 1) or blood pressure compared with the effects of saline inhalation.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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This study demonstrates that formoterol inhibits the plasma extravasation induced by histamine in the main bronchi but not in the trachea with ozone-induced inflammation. Salbutamol inhibits it neither in the main bronchi nor in the trachea after ozone. In contrast, in both the trachea and main bronchi salbutamol and formoterol each reduced the histamine-induced bronchoconstriction even in the guinea pigs exposed to ozone. In the dry air-exposed animals that served as control, salbutamol and formoterol each significantly reduced both the histamine-induced bronchoconstriction of plasma extravasation.
The reason for the weak antipermeability effects of these
2-agonists in the inflamed airways is not clear. Considering
the presence of 2-adrenergic receptors on endothelial cells,
the target for the antipermeability action of 2-agonists is
likely to be the endothelial cells of the postcapillary venules
and collecting venules (8). One possibility is cellular heterogeneity of 2-receptor turnover in the different lung cells (23),
such as cells of the endothelium and airway smooth muscle. In
airway smooth muscle, the density of the -receptor is relatively low, whereas the density of its mRNA is very high. This
indicates either that the rate of receptor synthesis is high and
the turnover of receptors is rapid or that the stability of mRNA
is high. By contrast, the alveolar walls exhibit a very high receptor density but a low level of its mRNA, suggesting that it
is difficult to downregulate -receptors in the airway smooth
muscle. Cellular heterogeneity in the reduction of -receptor
density in different lung cells following various stimuli also has
been reported (24, 25, 26). For example, in a model of atopy
induced by Haemophilus influenzae, there was a reduction in
the -receptor density in the airway epithelium and lung parenchyma but not in the airway sooth muscle (25). After ozone
exposure, inflammatory mediators (27) may reduce the number
of 2-receptors and impair their function. Decreases in the
number and function of 2-receptors may differ in the smooth
muscle cells and the endothelial cells.
In the guinea pigs exposed to ozone, formoterol had a more
profound inhibitory effect on histamine-induced microvascular
leakage in the bronchi than in the trachea. This difference may
be related to the anatomic distribution of -receptors in the
airways. The peripheral airways are rich in -receptor density
compared to the central airways (28). We consider that -receptors may be distributed more densely in the peripheral than in
the central airways, even after the down-regulation of -receptors by the exposure to ozone.
We observed differing effects of formoterol and salbutamol
on the histamine-induced plasma leakage in the inflamed airways after the exposure to ozone. Formoterol is reportedly more
potent than salbutamol in inhibiting both the airway microvascular leakage and bronchoconstriction induced by histamine (4,
5). In the present study, 0.5 mg/ml formoterol and 5 mg/ml
salbutamol aerosol each reduced bronchoconstriction to a
similar extent after histamine inhalation in both the dry-air
and ozone-exposed animals. Furthermore, we studied with a
larger dose of salbutamol in ozone-exposed animals. At least
in the doses of these 2-agonists that inhibit bronchoconstriction, salbutamol did not affect plasma leakage, whereas formoterol did. The reasons for the different antipermeability effects of these two 2-agonists in inflamed airways may be
related to differences in their antipermeability potency ratio
and smooth muscle relaxant potency ratio (3).
The vascular antipermeability effects of 2-agonists may be
dependent on the degree of increased permeability. 2-agonists have been shown to reduce the microvascular leakage in
the airways induced by histamine or bradykinin. In these studies, the leakage was increased 3 to 13 times of baseline values by
histamine or bradykinin (3, 5, 7). In the present study, the degree of increased leakage induced by histamine was two to four times that of baseline values after ozone exposure, which is within the
range to be able to be suppressed by 2-agonists. Furthermore, plasma leakage was reduced by formoterol in the bronchi even
after ozone. We consider that the present study does not simply
reflect the amplitude of histamine-induced microvascular leakage in ozone-exposed animals.
In the bronchial circulation, 2-agonists dilate the blood
vessels and increase blood flow (13). These agents may exacerbate airway microvascular leakage by increasing blood flow
to leaky vessels in inflamed airways. However, in our study,
formoterol reduced microvascular leakage in the main bronchi but not in the trachea with inflammation induced by
ozone. Long-acting 2-agonists have been shown to be more
potent than salbutamol in inhibiting the release of mediators
from inflammatory cells (29, 30). In addition, long-acting 2-agonists inhibit the late asthmatic response to antigen challenge (31), an effect thought to persist beyond the period
of protective action on airway smooth muscle (33). Along with
such evidence of the anti-inflammatory properties of long-acting 2-agonists, our findings could indicate a beneficial effect
of these drugs in the treatment of airway inflammatory diseases.
It was suggested by Erjefält and Persson that the tissue content of Evans blue dye most likely reflects intravascular dye, at least in control animals (34). They demonstrated the failure of the washing technique, because only about 60% of the blood pool of airway tissue samples was washed away after aorta perfusions with 100 ml fluid. In the present study, animals were perfused with 500 ml saline at a pressure of 120 mm Hg until the perfusate became clear. We consider that this washing is enough to remove intravascular dye from bronchial circulation. In recent studies, Evans blue were used as the marker of plasma leakage in the airways (5, 35).
Evans blue dye was used as the marker of plasma leakage in the present study. The effects of other factors, such as luminal entry and lymphatic clearance, on the tissue contents of dye remains unknown. Furthermore, Evans blue is a highly diffusible molecule and may dissociate from albumin and diffuse back into the vascular space once in the interstitium. Further investigations are needed to clarify the epithelial permeability of dye in the inflamed airways after ozone.
Ozone exposure per se slightly increased microvascular
leakage in the airways, and inhaled salbutamol and formoterol
failed to inhibit it. The failure in the reversal of microvascular
leakage by 2-agonists may be due to the sequence and timing
of stimulation and 2-agonists inhalation. In the present study,
2-agonists were administered after ozone exposure but not
before ozone.
In conclusion, we showed that formoterol, but not salbutamol, reduces the microvascular leakage induced by histamine
in guinea pig airways with ozone-induced inflammation. The
difference between these two 2-agonists deserves further
study. The anti-inflammatory properties of formoterol could
contribute to a beneficial effect in the treatment of airway inflammatory diseases.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Hisamichi Aizawa, M.D., Research Institute for Diseases of the Chest, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-82, Japan.
(Received in original form June 5, 1996 and in revised form May 5, 1997).
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References |
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INTRODUCTION
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DISCUSSION
REFERENCES
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