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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Endothelin-1 (ET-1) has recently been reported to have a potential pathophysiologic role in bronchial
asthma. In the current study, we hypothesized whether ET-1 and a gene encoding ET-1 might be involved in airway hyperresponsiveness (AHR), which is a major feature of bronchial asthma. To test
this hypothesis, we investigated airway responsiveness in ET-1+/
heterozygous knockout mice,
which genetically produce lower levels of ET-1, and in ET-1+/+ wild-type mice. Airway responsiveness
was assessed through the concentration of an agonist required to double lung resistance (EC200 RL).
Unexpectedly, airway responsiveness to methacholine was markedly enhanced in ET-1+/ heterozygous
mice as compared with ET-1+/+ wild-type mice (EC200 RL: 1.8 ± 0.1 versus 21.6 ± 5.6 mg/ml, p < 0.002).
Pretreatment with the nitric oxide (NO) synthase inhibitor Ng-monomethyl-L-arginine (L-NMMA) significantly enhanced methacholine responsiveness in ET-1+/+ wild-type mice, but not in ET-1+/ heterozygous mice. Meanwhile, there was no difference between ET-1+/ heterozygous mice and the
wild-type mice in airway responsiveness to 5-hydroxytryptamine (5-HT). In sensitized mice, no significant differences in responsiveness to antigen were observed between the two groups. These findings suggest that the gene encoding ET-1 may be potentially involved in the etiology of airway hyperreactivity, and that the decrease in ET-1 concentration is associated with AHR to methacholine. In
mice, ET-1 as well as NO may have a significant role in the homeostasis of airway physiology.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Endothelin-1 (ET-1) is a 21-amino-acid constrictor peptide isolated from vascular endothelial cells (1). ET families (ET-1, ET-2, and ET-3) act on two G-protein-coupled receptors (2, 3), and ET-1 has been shown to be one of the most potent agonists of both vascular and airway smooth muscle (4). It has recently been postulated that ET-1 may have a potential pathophysiologic role in bronchial asthma (8). Meanwhile, it has been reported that ET-1 is essential to normal embryonic development (11). In the cardiovascular system, ET-1 has physiologic roles in normal development and in maintaining homeostasis (12). It has been shown that ET-1 not only has a pressor effect, but also a depressor effect via stimulation of nitric oxide (NO) production (13). However, in the respiratory system, physiologic roles of ET-1 remain to be clarified.
Airway hyperresponsiveness (AHR) is one of the most important traits of bronchial asthma. It is postulated that genetic factors contribute significantly to the etiology of AHR (14- 16). On the basis of its inheritance pattern, AHR is considered to be under the control of complex genes (14). Recently, it has been reported that multiple genetic loci are associated with AHR in mice, according to quantitative locus analysis (17). To identify genes responsible for AHR, it may also be useful to analyze specific gene-disrupted, knockout mice.
In the current study, we hypothesized that ET-1 and a gene
encoding ET-1 might be involved in AHR, which is a major
feature of bronchial asthma. To test this hypothesis, we investigated airway responsiveness in ET-1+/ heterozygous knockout mice, which genetically produce lower levels of ET-1 (11),
and in ET-1+/+ wild-type mice. Since ET-1 has been reported
to have a significant role in asthma (8), we initially speculated that the decrease in ET-1 concentration would reduce
airway responsiveness in mice. However, we observed that
airway responsiveness to methacholine was markedly enhanced in ET-1+/ heterozygous mice as compared with ET-1+/+ wild-type mice, whereas there was no significant difference in airway responsiveness to 5-hydroxytryptamine (5-HT).
On the basis of reports that ET-1 per se stimulates the production of NO (13), we also studied the effects of inhibiting NO
synthesis on airway responsiveness in the current knockout
model.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Knockout Mice
ET-1 knockout mice were established by gene targeting (11). Mice
with the genetic background of the 129Sv/J × ICR hybrid were backcrossed to ICR mice to achieve a uniform genetic background. These
mice (more than 10th generation of backcross), heterozygous for the
Edn 1 mutant allele, were mated. The animals were maintained on a
light-dark cycle, with light from 9:00 A.M. to 9:00 P.M. at 25° C. Mice
were fed with a normal diet and water ad libitum. Offspring were genotyped at 3 wk of age. For genotyping, genomic DNAs were isolated
from biopsied tail and subjected to 28 cycles of amplification with the
polymerase chain reaction (PCR) (1 min at 95° C; 1 min at 60° C; 1 min
at 72° C). The primers were sense: 5'-TGTCTTGGGAGCCGAACTCA-3', and antisense: 5'-GCTCGGTTGTGCGTCAACTTCTGG-3'.
The PCR product consisted of 537 bp.
In a previous study (11), we demonstrated that there are significant differences between the heterozygous mice and wild-type mice in
the concentrations of ET-1 (plasma: 1.13 ± 0.18 versus 1.87 ± 0.22 pg/
ml; lung: 70.0 ± 7.5 versus 153.1 ± 12.6 pg/mg protein). As previously
reported (11), no viable ET-1/ homozygotes were observed. Eight-
to 11-wk-old male littermates (ET-1+/+ or ET-1+/) were used in this
study.
Animal Preparation
Animals were anesthetized with pentobarbital sodium (25 mg/kg intraperitoneally) and ketamine hydrochloride (25 mg/kg intraperitoneally) in combination, and then paralyzed with pancuronium bromide (0.3 mg/kg intraperitoneally). Anesthesia and paralysis were maintained by supplemental administration of 10% of the initial dose every hour. After tracheostomy, a metal endotracheal tube (ID = 1 mm, length = 8 mm) was inserted in the trachea. Animals were mechanically ventilated (Model 683; Harvard Apparatus, South Natick, MA) with tidal volumes of 8 ml/kg and frequencies of 2.5 Hz. The thorax was widely opened by means of midline sternotomy, and a positive end expiratory pressure (PEEP) of 3 cm H2O was applied by placing the expiration line underwater. During the experiments, oxygen gas was continuously supplied to the ventilatory system. Under these ventilatory conditions, arterial pH, PO2, and PCO2 were 7.35 to 7.45, 100 to 180 mm Hg, and 30 to 45 mm Hg, respectively, at the end of experiments (Compact 3; AVL Medical Systems, Switzerland). A heating pad was used to maintain the body temperature of animals.
Tracheal pressure was measured with a piezoresistive microtransducer (Model 8510B-2; Endevco, San Juan Capistrano, CA) placed in the lateral port of the tracheal cannula. Tracheal flow was measured by means of a Fleisch pneumotachograph (Model 00000; Lausanne, Switzerland). All signals were amplified, filtered at a cutoff frequency of 100 Hz, and converted from analogue to digital format with a converter (DT2801-A; Data Translation Inc., Marlborough, MA). The signals were sampled at a rate of 200 Hz and stored on an IBM-AT (IBM Inc., Armonk, NY) compatible computer.
Lung resistance was measured as previously described (18). The tracheal pressure was corrected for both the tube resistance and the Bernoulli effect (19). From flow, volume, and corrected tracheal pressure (Ptr) data, lung elastance (EL) and total lung resistance (RL) were calculated by finding the best fit for the equation of both inspiratory and expiratory motion:
|
(1) |
where K is a constant whose value was also estimated by multiple linear regression, and was less than 0.5 cm H2O different from the real value of PEEP.
Airway Responsiveness to Methacholine Administration
In eight heterozygous mice and seven wild-type mice, inhalations of saline and methacholine (MCh) were administered at a PEEP of 3 cm H2O. At the start of the protocol, two deep inhalations (three times VT) were delivered to standardize the volume history. All animals were then challenged with saline aerosol for 2 min. Aerosols were generated with an ultrasonic nebulizer (Ultra-Neb100; DeVilbiss, Somerset, PA) and delivered through the inspiratory line into the trachea. Measurements of 10 s duration were made during tidal ventilation beginning at 1 min after administration of saline aerosol. This represented the baseline measurement. Following this, each dose of MCh aerosol was administrated for 2 min in a dose-response manner (0.31 to 80 mg/ml). Airway responsiveness was assessed with the concentration of MCh required to double lung resistance (EC200 RL), which was calculated by interpolation.
Effects of NO Synthesis Inhibition on Airway Responsiveness to MCh
We studied the effects of NO synthase inhibition on airway responsiveness, using Ng-monomethyl-L-arginine (L-NMMA). Five minutes prior
to the protocol, 250 µmol/kg L-NMMA was administered intravenously
to ET-1+/ heterozygous mice (n = 6) and ET-1+/+ wild-type mice (n =
5). Saline and MCh aerosols were then administered, and airway responsiveness was assessed in the same manner as described earlier.
Airway Responsiveness to 5-HT Administration
Airway responsiveness to 5-HT was examined in ET-1+/ mice (n = 5) and ET-1+/+ mice (n = 4). Following saline aerosol inhalation, each
dose of 5-HT aerosol was administered for 2 min in a dose-response manner (0.15 to 20 mg/ml). Airway responsiveness was assessed through EC200 RL.
The effects of NOS inhibition on airway responsiveness to 5-HT
were also studied in ET-1+/ (n = 5) and ET-1+/+ mice (n = 4). After
intravenous pretreatment with 250 µmol/kg L-NMMA, saline and
5-HT aerosols were administered and airway responsiveness was assessed in the same manner as described earlier.
Airway Responsiveness to Antigen
Mice 6 to 7 wk of age were actively sensitized with an intraperitoneal injection of 1 ml of a sterile suspension of 0.1 mg ovalbumin (OA) and 10 mg of aluminum hydroxide in saline. As an adjuvant, 0.1 ml of Bordetella pertussis vaccine (6 × 108 heat-killed bacilli) was administered intraperitoneally at the time of sensitization. Animals were studied 18 to 20 d after sensitization.
Following two deep inhalations, all animals were challenged with saline aerosol for 5 min. Measurements of 10 s duration were made beginning at 1 min after administration of saline aerosol as the baseline measurement for each group. Aerosols of saline or OA solution (5% wt/vol in saline, prepared immediately before each experiment) were then administered for 5 min. In each group, measurements were made every minute for 10 min after aerosol administration, and were repeated at 5-min intervals for up to 30 min.
Materials and Chemicals
MCh, 5-HT, L-NMMA, and OA were purchased from Sigma Chemical Co. (St. Louis, MO). Aluminum hydroxide and Bordetella pertussis vaccine were obtained from Wako Chemical (Osaka, Japan).
Data Analysis
Intergroup comparisons of the experimental groups' physiologic data were made with analysis of variance (ANOVA) (Scheffe's test). Data are expressed as mean ± SE. Values of p < 0.05 were taken as significant.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Airway Responsiveness to MCh Administration
There were no significant differences in baseline RL between
ET-1+/ and ET-1+/+ mice (0.389 ± 0.013 versus 0.368 ± 0.014 cm H2O/ml/s). Figure 1 demonstrates MCh concentration-response curves in the two groups. Each dose of MCh induced a
greater response in ET-1+/mice than in ET-1+/+ mice. EC200
RL in ET-1+/ heterozygous mice was significantly smaller
than that in ET-1+/+ wild-type mice (1.8 ± 0.1 versus 21.6 ± 5.6 mg/ml, p < 0.002), suggesting that airway responsiveness
in ET-1+/ heterozygous mice was increased over that in ET-1+/+ wild-type mice.
|
Effects of NOS Inhibition on Airway Responsiveness to MCh
The administration of L-NMMA elicited modest but significant increases in airway basal tone in both study groups of
mice (Table 1). Figure 2 shows MCh concentration-response
curves after the administration of L-NMMA. There were no
differences in airway responses at each dose of MCh. The effects of NOS inhibition on airway responsiveness are summarized in Figure 3. Pretreatment with L-NMMA significantly
enhanced airway responsiveness in ET-1+/+ wild-type mice,
but not in ET-1+/ heterozygous mice.
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Airway Responsiveness to 5-HT Administration
Figure 4 summarizes 5-HT airway responsiveness in each
group. There were no differences between ET-1+/ and ET-1+/+
mice in airway responses to 5-HT. Pretreatment with L-NMMA
did not affect 5-HT responsiveness in either ET-1+/ or ET-1+/+ mice.
|
Airway Responsiveness to Antigen
There were no significant differences in baseline RL between
the two study groups of mice. Figure 5 represents the responses to saline or antigen in each group of sensitized mice. Although antigen-induced airway responses were observed in both groups, there were no significant differences in airway responses between the ET-1+/ heterozygous mice and ET-1+/+ wild-type
mice.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of the current experiments show that airway responsiveness to MCh was markedly enhanced in ET-1+/ heterozygous mice as compared with ET-1+/+ wild-type mice.
Pretreatment with L-NMMA significantly enhanced MCh airway responsiveness in ET-1+/+ wild-type mice but not in ET-1+/ heterozygous mice. There was no difference between ET-1+/ heterozygous mice and wild-type mice in airway responsiveness to 5-HT. In sensitized mice, no significant differences
in responsiveness to antigen were observed between the two
groups. These findings suggest that a decrease in ET-1 concentration may induce AHR to MCh, which is one of the cardinal
characteristics of asthma.
Before we discuss the results of the study, technical issues
warrant consideration. In the current protocol, we studied ET-1+/ heterozygous knockout mice, not ET-1/ homozygous
mice. Apparently, ET-1/ homozygous knockout mice would
be most desirable for testing the present hypothesis that ET-1
and the gene encoding ET-1 might be associated with AHR.
However, as previously reported (11), no viable ET-1/ homozygous mice were found when offspring were genotyped at
3 wk of age; the ET-1/ homozygous mice died of apnea at
birth. In contrast, all ET-1+/ heterozygous mice were viable,
but ET-1 levels in the lungs of ET-1+/ heterozygous mice
were reduced by 55% as compared with those in wild-type
mice (11). We therefore used ET-1+/ heterozygous mice and
littermate wild-type controls to perform this study.
Enhanced airway responsiveness to MCh in ET-1+/ heterozygous mice might be an unexpected finding. Recently, it
has been postulated that ET-1 may play an important pathophysiologic role in asthma (8), pulmonary inflammation
(23), and pulmonary vascular disease (24). In asthmatic individuals, it has been shown that the concentration of ET-1 in
bronchoalveolar lavage fluid (BALF) is related to the severity
of lung functional impairment (9). The level of ET-like immunoreactivity in biospied airway epithelium from asthmatic individuals is significantly greater than that from nonasthmatic
controls (10). On the basis of previous studies, we initially
speculated that airway responsiveness in ET-1+/ mice, which
genetically produce lower levels of ET-1 than do wild-type
mice, might be reduced in comparison with wild-type controls.
However, the current study showed that the decrease in ET-1
level enhanced airway responsiveness to MCh, which seems a
paradoxical finding.
A possible mechanism for this paradoxical phenomenon is
that the deficiency in ET-1 influences the metabolism of mediators other than ET-1. It has been reported that ET-1 stimulates the release of NO, which is a dilator of vascular and airway smooth muscle (13). The decrease in ET-1 throughout
development and life may downregulate the production of
bronchodilating mediators such NO, resulting in the unexpected observed MCh hyperresponsiveness in ET-1+/ mice.
To examine this possibility, we studied the effects of the NOS
inhibitor L-NMMA on airway responsiveness in ET-1+/+ and
ET-1+/ mice. The administration of L-NMMA provoked
modest albeit significant increases in airway basal tone in both
groups, whereas it enhanced airway responsiveness to MCh in
ET-1+/+ mice but not in ET-1+/ mice. In guinea pigs, it has
been reported that NOS inhibitors including L-NMMA induce
an increase in basal tone and AHR (25), which is compatible
with the current findings in wild-type mice. However, in ET-1+/ heterozygous mice, L-NMMA did not affect airway responsiveness to MCh. Of note was that L-NMMA-pretreated
ET-1+/+ mice expressed a similar degree of airway hyperresponsivness to MCh as that observed in ET-1+/ mice. These
findings suggest that the decrease in ET-1 causes the observed
MCh hyperresponsiveness in ET-1+/ mice, and that this observation might be associated with the reduction of NO synthesis. However, the exact mechanism for the hyperresponsiveness to MCh remains to be clarified and warrants further
research.
There were no significant differences between the ET-1+/
mice and the wild-type mice in airway responsiveness to 5-HT.
Inhibition of NO synthesis had no effects on 5-HT responsiveness in either heterozygous or wild-type mice. These observations suggest that the ET-1+/ heterozygous mice are specifically hyperresponsive to MCh but not to 5-HT. Recently,
Levitt and Mitzner showed (16) that AHR to 5-HT and acetylcholine is inherited independently in mice, and that murine
nonspecific AHR is determined by multiple genes. In the current study, it seems that the ET-1 mutant mice exhibited muscarinic receptor-specific hyperresponsiveness, but not general bronchial hyperresponsiveness.
This study indicates that a decrease in ET-1 does not affect
antigen-induced bronchoconstriction. After active sensitization, ET-1+/ heterozygous mice and ET-1+/+ wild-type mice
exhibited a similar degree of responsiveness to antigen, suggesting that the reduced production of ET-1 may play little
part in acquired-type bronchial asthma.
It is postulated that hereditary factors contribute to the etiology of asthma. The inheritance pattern suggests that a number of complex genes are involved in the pathogenesis of bronchial asthma (14). It would be difficult to identify asthma genes among 60,000 to 80,000 human genes (26). Since AHR in the mouse resembles human asthma (15, 16), murine models of asthma have been extensively used to approach candidate genes and loci (17). Recently, transgenic or knockout mice have also been used to examine potential asthma-related genes encoding bioactive mediators (27, 28). On the basis of reports that ET-1 may be associated with bronchial asthma (8), genes that regulate the function and metabolism of ET-1 may be potentially associated with the etiology of asthma. The ET-1-related genes include the genes encoding ET-1 ligand and ET receptors (1). The current observations suggest that normal function of the ET-1 gene and physiologic levels of ET-1 are important in preventing the induction of AHR. The knockout mice in the present study, which genetically produce lower levels of ET-1 throughout development and life, may be useful for studying the genetic contribution of ET-1 to the etiology of asthma. Meanwhile, whether overexpression of the ET-1 gene may affect airway responsiveness remains to be elucidated. In addition, since the human ET-1 gene maps to chromosome 6 (29), the linkage to chromosome 6 and AHR in humans might warrant further study.
Recently, it was reported that ET-1 has both physiologic
and pathophysiologic importance. Kurihara and colleagues
(11) demonstrated that ET-1/ homozygous mice represent
morphologic abnormalities of the pharyngeal arch-derived
craniofacial tissues and organs, indicating that ET-1 is essential to normal embryonic development. They also reported that ET-1-homozygous knockout mice display cardiovascular
malformations including aortic arch malformations and ventricular septal defect, and that the frequency and extent of
these abnormalities are increased by antagonism of the ETA
receptor (12). ET-1+/ heterozygous mice develop high blood
pressure, suggesting that ET-1 may have an important role in
the cardiovascular system in maintaining homeostasis (11).
However, the pathophysiologic importance of ET-1 is little
known in the respiratory system. The observations in the current study suggest that ET-1 has an important role in regulating airway function.
In summary, ET-1+/ heterozygous mice, which generate
lower levels of ET-1 than do ET-1+/+ wild-type mice, develop
AHR to MCh. An NOS inhibitor increased airway responsiveness to MCh in ET-1+/+ wild-type mice, but not in ET-1+/
heterozygous mice. Meanwhile, no significant difference in responsiveness to 5-HT was observed between ET-1+/ heterozygous mice and wild-type mice. Following active sensitization, there were no differences in antigen-induced bronchoconstriction between the two groups. These findings suggest that the
gene encoding ET-1 may be involved in the etiology of AHR,
and that the decrease in ET-1 concentration induces AHR to
MCh. In mice, ET-1 as well as NO may have a significant role
in physiologic airway homeostasis.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. T. Nagase, Department of Geriatrics, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan, 113.
(Received in original form June 2, 1997 and in revised form September 16, 1997).
Acknowledgments: Supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan.
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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 T. NAGASE, S. ISHII, H. SHINDOU, Y. OUCHI, and T. SHIMIZU Airway Hyperresponsiveness in Transgenic Mice Overexpressing Platelet Activating Factor Receptor Is Mediated by an Atropine-Sensitive Pathway Am. J. Respir. Crit. Care Med., January 15, 2002; 165(2): 200 - 205. [Abstract] [Full Text] [PDF]
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 G. Hansen, S.-L. C. Jin, D. T. Umetsu, and M. Conti Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D PNAS, June 6, 2000; 97(12): 6751 - 6756. [Abstract] [Full Text] [PDF]
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T. Nagase, H. Kurihara, Y. Kurihara, T. Aoki-Nagase, R. Nagai, and Y. Ouchi Disruption of ET-1 gene enhances pulmonary responses to methacholine via functional mechanism in knockout mice J Appl Physiol, December 1, 1999; 87(6): 2020 - 2024. [Abstract] [Full Text] [PDF]
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