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Vol. 83, Issue 6, 1884-1889, December 1997
1-adrenergic
agonists
1 Department of Environmental Health Sciences, Division of Physiology, The Johns Hopkins University, Baltimore, Maryland 21205; and 2 First Department of Internal Medicine, Nihon University School of Medicine, Tokyo, 173 Japan
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Freed, Arthur N., Varsha Taskar, Brian Schofield, and
Chiharu Omori. Hyperventilation-induced airway injury and vascular leakage in dogs: effects of
1-adrenergic agonists.
J. Appl. Physiol. 83(6):
1884-1889, 1997.
1-Adrenergic agonists
inhibit hyperventilation-induced bronchoconstriction (HIB) in dogs. We
tested the hypothesis that -agonists inhibit HIB by
reducing bronchovascular leakage and edema that theoretically could
cause airway obstruction. Peripheral airways were isolated by using a
bronchoscope; pretreated with either methoxamine (Mx), norepinephrine
(NE), or saline aerosol; and then exposed to a 2,000 ml/min dry-air
challenge (DAC) for 2 min. Colloidal carbon was injected before DAC and
used to quantify bronchovascular permeability. Mx-, NE-, and
vehicle-treated airways were prepared for morphometric analysis within
1 h after DAC. Light microscopy revealed that the 2-min DAC produced
minimal bronchovascular leakage and little epithelial damage. However, pretreatment with either Mx or NE significantly enhanced dry
air-induced bronchovascular hyperpermeability and mucosal injury. The
increased damage associated with these
1-agonists implicates a
protective role for the bronchial circulation. The fact
that 1-agonists inhibit HIB
suggests that neither dry air-induced leakage nor injury directly
contributes to the development of airway obstruction. In addition,
our data suggest that
-agonists attenuate HIB in part by
augmenting hyperventilation-induced bronchovascular leakage and by
replacing airway water lost during a DAC.
bronchovascular permeability; exercise-induced asthma; goblet
cells; hyperventilation-induced bronchoconstriction; mast cells
INTRODUCTION HYPERVENTILATION-INDUCED bronchoconstriction (HIB) in
canine peripheral airways resembles in many respects hyperpnea- or
exercise-induced asthma in human subjects. The time course over which
HIB develops and subsides and the responses to variations in stimulus
strength and duration are remarkably similar (11, 17). HIB is also associated with airway epithelial cell damage (14, 15, 31) and the
release of biochemical mediators in dogs (15, 24, 31) and asthmatic
humans (9, 22, 30) alike.
Hyperventilation with dry air increases evaporative water loss.
Subsequent increases in local airway fluid osmolarity may then trigger
mast cell degranulation and airway smooth muscle constriction (1).
Studies of asthmatic subjects provide indirect evidence suggesting that
In the present study, we tested the hypothesis that
METHODS Experimental Techniques
1-agonists diminish either
hyperpnea-induced microvascular hyperperfusion, engorgement,
bronchovascular leakage, or edema formation (8, 18). However, there
remains a dearth of data demonstrating that any of these events
actually contribute to the development of HIB in asthmatic patients.
Hyperventilation with dry air does increase bronchovascular blood flow
(2) and permeability (14) in dogs and may cause airway narrowing via bronchovascular congestion, leakage, and the formation of edema. Theoretically, 1-adrenergic
agents can protect against HIB by inhibiting the development of these
phenomena.
1-adrenergic agonists inhibit
HIB by reducing bronchovascular hyperpermeability. Methoxamine (Mx) and
norepinephrine (NE) were selected for use in this study because each
has been shown to be effective in inhibiting hyperpnea-induced airway
obstruction in human asthmatic subjects (8, 18) and in canine
peripheral airways (25). However, we found that both drugs enhance
bronchovascular permeability, indicating that airway microvascular
leakage is unlikely to play a pivotal role in the development of HIB.
4.5 mm in diameter were excluded because of
their proximity to the bronchoscope (~5-mm diameter). Control airways
were obtained from unwedged sublobar segments that were not exposed to
DAC but were located adjacent to a challenged sublobar segment. All
airway cross sections were categorized as either bronchi (with
cartilage) or bronchioles (without cartilage). The relative condition
of the airway mucosa was assigned to one of three categories for analysis: normal mucosa containing ciliated and goblet cells (C + G),
normal mucosa containing primarily ciliated cells (C 
G), and
damaged mucosa composed of either nonciliated or denuded airway surfaces (14). The perimeter of the basement membrane
(PBM) and the
lengths of perimeter containing C + G, C G, and
damaged mucosa were measured.
PBM was used to
calculate the maximally relaxed bronchial diameter
(D = PBM/
).
Four to six cross sections were evaluated from each experimental
sublobar segment, and two airway cross sections were examined from each
control segment. Measurements were made on each airway cross section at
a magnification of ×400, and the overall average per sublobar
segment was calculated for each treatment. Ciliated cells per
millimeter and goblet cells per millimeter of basement membrane were
counted in C + G and C G mucosa of PAS-stained tissues, and
goblet-to-ciliated cell (G/C) ratios were calculated. Goblet cells were
identified by their shape and affinity for PAS. The numbers of mast
cells in the lamina propria and submucosa of the bronchial wall located directly below either normal or damaged mucosa were counted in cross
sections stained with TB. Mast cells were identified as cells that had
granules stained with TB. Mast cell density was expressed as number per
square millimeter of lamina propria or submucosa located below either
normal or damaged mucosa. The area of colloidal carbon in the vascular
wall of vessels located under either normal ciliated or damaged mucosa,
expressed as square micrometers per square millimeter of airway tissue,
was used to quantify microvascular leakage in the lamina propria and
submucosa of each airway cross section (14, 27).
Experimental Protocol
After establishing a stable baseline Pb, DAC was performed in a sublobar segment ~15 min after pretreatment with either aerosolized saline, Mx, or NE. Baseline Pb was recorded after aerosol delivery, and colloidal carbon (1 ml/kg) was injected into the femoral vein 1-2 min after DAC was completed. Dogs were exsanguinated 15 min after DAC.Statistical Analyses
Morphometric data were evaluated by using either a Mann-Whitney U-test or the Kruskal-Wallis one-way analysis of variance for comparison of treatment means. Nonparametric multiple comparisons were done by using Dunn's test. All values were expressed as means ± SE, and statistical significance was judged as P < 0.05.RESULTS
A total of 134 airway cross sections from 9 dogs were examined. The average diameters of bronchi and bronchioles were 3.5 ± 0.11 (n = 54) and 1.8 ± 0.09 mm (n = 80), respectively. Pretreatment with vehicle and NE was done in four dogs; five dogs were pretreated with Mx. Neither vehicle nor NE aerosol significantly altered either mean arterial pressure (MAP; 153 ± 10 vs. 150 ± 11 mmHg; P = 0.885) or HR (153 ± 20 vs. 168 ± 16 beats/min, n = 4; P = 0.686). Similarly, pretreatment with Mx did not significantly affect MAP (127 ± 10 vs. 127 ± 11 mmHg, P = 1.0) or HR (162 ± 13 vs. 132 ± 17 beats/min, n = 5; P = 0.309). All measurements made on unexposed control airways from both groups were similar and were combined (n = 9) for statistical analyses.
Hyperventilation-Induced Mucosal Damage
The percent of airway perimeter occupied by C + G, C G, and damaged mucosa in control and challenged bronchi and bronchioles is summarized in Table 1. Although DAC did
not significantly increase dry air-induced damage in vehicle-treated
bronchi, mucosal injury was significantly greater
(P < 0.05) in NE- and Mx-treated bronchi compared with control bronchi (Fig.
1). No significant mucosal injury was
evident in any DAC bronchioles compared with controls.
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Hyperventilation-Induced Goblet Cell Secretion
The number of ciliated cells per millimeter of basement membrane in unchallenged control, DAC vehicle-treated, DAC NE-treated, and DAC Mx-treated bronchi were similar (Fig. 2). The number of goblet cells per millimeter of basement membrane was also similar for bronchi in all four groups: unchallenged control (26 ± 5 cells/mm2), DAC vehicle-treated (23 ± 6 cells/mm2), DAC NE-treated (24 ± 4 cells/mm2), and DAC Mx-treated (24 ± 7 cells/mm2). The bronchioles showed similar trends. DAC did not alter G/C (Fig. 2).
Dry Air-Induced Changes in Mast Cell Number
The number of mast cells per square millimeter of lamina propria in control, vehicle-treated, NE-treated, and Mx-treated bronchi and bronchioles were similar (Fig. 3). No differences were detected in the number of submucosal mast cells in either bronchi or bronchioles. No significant differences were detected in mast cell number per square millimeter of lamina propria located below C + G, C G, and damaged mucosa.
Dry Air-Induced Bronchovascular Hyperpermeability
Regardless of mucosal condition, negligible quantities of colloidal carbon were observed within the walls of vessels in the lamina propria of control bronchi and bronchioles (Fig. 4). Although not statistically significant, the density of colloidal carbon tended to increase from 117 ± 35 µm2/mm2 in control bronchi to 577 ± 248 µm2/mm2 in DAC-exposed vehicle-pretreated bronchi. Colloidal carbon was increased to 2,291 ± 704 and 4,092 ± 1,101 µm2/mm2 (P < 0.05) in DAC-exposed bronchi pretreated with either NE or Mx, respectively. No significant difference existed between the NE- and Mx-treated airways. DAC did not significantly increase bronchovascular permeability in bronchioles.
Dry air-induced vascular leakage in the lamina propria was also
examined as a function of the condition of the overlying mucosa regardless of airways size (Fig.
5). The density of colloidal carbon located below normal ciliated mucosa in control airways was 192 ± 53 µm2/mm2.
Of the three pretreatment groups, only Mx had colloidal carbon located
below C + G mucosa significantly increased above control levels (765 ± 238 µm2/mm2,
P < 0.05). Colloidal carbon located
below C G mucosa in DAC-exposed vehicle-treated (984 ± 241 µm2/mm2)
and Mx-treated (1,973 ± 1,035 µm2/mm2)
airways were significantly increased when compared with normal mucosa
in control airways (P < 0.05).
Finally, extravasation of carbon beneath damaged mucosa in
vehicle-treated (1,358 ± 258 µm2/mm2),
NE-treated (1,860 ± 351 µm2/mm2), and Mx-treated
(4,001 ± 146 µm2/mm2)
airways was significantly increased when compared with normal mucosa in control airways (P < 0.05). Despite obvious trends, no significant difference between
treatments was detected (P > 0.413).
G)], and damaged
(Dam) mucosal epithelium in Con, Veh-, NE-, and Mx-treated airways.
Values are means ± SE. * P < 0.05 compared with normal control (C + G) mucosa.
DISCUSSION
We previously reported that pretreatment with
aerosolized Mx and NE reduces HIB in canine peripheral airways by ~25
and 60%, respectively (25). In that study, we concluded that NE
reduced HIB primarily via the stimulation of
2- and not
1-adrenergic receptors.
However, this finding does not exclude the possibility that
NE-stimulated 1-activity plays
a role in other related events. In contrast, Mx did attenuate HIB
via the stimulation of
1-adrenergic receptors. We
speculated that the modest inhibition produced by Mx resulted from
either increased mucus secretion (reducing evaporative water loss and
mucosal injury during DAC) or constriction of the bronchovasculature
(abating either hyperventilation-induced microvascular hyperperfusion,
engorgement, bronchovascular leakage, or edema formation). The
-component of NE is likely to produce similar changes.
In this morphometric analysis, unexposed control airways were composed
of normal ciliated epithelium and goblet cells, with an average of
~2% of the airway mucosa appearing damaged (Fig. 1, Table 1). Unlike
in previous studies that used 5-min rather than 2-min exposure times
(13, 14, 26, 27), DAC in the present study did not cause G/C (an
indicator of goblet cell degranulation and mucosal perturbation) to
decrease (Fig. 2). In fact, this 2-min DAC produced surprisingly little
damage to the airway mucosa (Fig. 1). We used a milder stimulus in
these experiments, because data from asthmatic subjects suggested that
Mx provided protection only from very mild episodes of HIB (8).
However, in contrast with our earlier speculations (25), pretreatment
with either Mx or NE enhanced DAC-induced mucosal injury: ~36% of
the perimeter of Mx-treated bronchi was injured, whereas ~47% of the
NE-treated perimeter was damaged after DAC (Fig. 1). The extent of this
mucosal injury is similar to our previously published results with the more potent 5-min stimulus (13, 14, 26, 27). Thus, assuming that Mx and
NE do constrict the bronchial circulation (6, 20), the resulting
reduction in bronchial blood flow is accompanied by a marked increase
in damage to the bronchial mucosa (Fig. 1). This observation is
consistent with our previous findings that 1) pretreatment with a
2-adrenergic agonist, which
presumably dilates the bronchial vasculature, significantly reduces
hyperventilation-induced mucosal injury (26) and
2) impairment of bronchial blood
flow enhances hyperventilation-induced mucosal injury
in canine airways (13). All of these studies indicate that the
bronchial circulation plays an important role in protecting the
bronchial mucosa from local injury during hyperventilation, possibly by
preventing dry air from entering the peripheral lung.
Unlike exposure to a 5-min DAC (13, 26, 27), 2 min of hyperventilation
did not significantly alter mast cell numbers in any airway examined in
this study. Treatment with neither Mx nor NE affected dry air-induced
mast cell degranulation in any region of the airway (Fig. 3). Mast cell
numbers did tend to be lower in Mx-treated bronchi, but this may
reflect degranulation in response to direct
1-receptor stimulation (19).
Previous studies suggest that mast cell degranulation either
contributes to or is a consequence of mucosal injury and plays an
important role in the development of HIB (13, 14, 26, 27). However, because our morphometric analysis focuses only on completely
degranulated mast cells, partial mast cell degranulation could account
for the observed effects without any reduction in mast cell number.
Several studies have reported that
1-agonists inhibit HIB in
asthmatic subjects (8, 18) and suggest that these drugs do so by
decreasing hyperventilation-induced microvascular hyperperfusion, engorgement, bronchovascular leakage, or edema formation.
NE in particular is believed to inhibit the development of HIB in
asthmatic subjects by reducing bronchial blood flow and, in so doing,
reducing the rate at which airways rewarm (18). However, human (23) and
canine (12) airways respond similarly to hyperventilation, and changes
in airway temperature in the absence of airway drying do not initiate
HIB in dogs (12). These observations suggest that abrupt thermal
changes are not a prerequisite for the initiation of HIB.
Hyperventilation with dry air does increase bronchial blood flow in
animals (2, 28) and results in bronchovascular hyperpermeability (13,
14). If either Mx or NE attenuated HIB by reducing bronchial blood
flow, then the bronchovascular leakage that accompanies HIB should also
be reduced. Although the milder stimulus used in this study did not
significantly increase vascular leakage in vehicle-treated airways, Mx
and NE markedly enhanced the hyperventilation-induced extravasation of
fluid compared with unchallenged control bronchi (Fig. 4).
Examination of mucosal-dependent vascular leakage reveals a striking
and progressive increase in fluid extravasation occurring below normal
ciliated mucosa replete with goblet cells (C + G), goblet cell-depleted
mucosa (C G), and damaged mucosa. This dose-response relationship between increasing level of perturbation (mucosal category) and the magnitude of bronchovascular leakage is most
obvious for Mx- and vehicle-treated airways (Fig. 5). In contrast, the
enhancing effect of NE seen when vascular leakage is quantified without
regard to mucosal condition (Fig. 4) is no longer obvious when analyzed
by mucosal category, suggesting that NE primarily affects vessels that
reside in damaged regions. Although the differences between vehicle-,
NE-, and Mx-treated airways are not statistically different, the
positive trend seen in Fig. 5 clearly shows that neither Mx nor NE
decreases bronchovascular permeability in DAC canine peripheral airways
and may actually enhance it. This is most obvious in vessels located
below normal (C + G) mucosa, where only Mx-treated airways exhibit a
significant increase in microvascular leakage. The greater efficacy in
all mucosal categories of Mx compared with NE may directly reflect the
greater 1-specificity of this
drug (25).
Our results are markedly different from those obtained in studies of
guinea pigs, showing that
1-agonists inhibit
microvascular leakage produced by histamine (29) and
platelet-activating factor (5). This inconsistency may result from
differences in either stimulus or species. In rats (21), inhaled Mx
inhibits substance P-induced microvascular leakage, presumably by
reducing bronchial blood flow. Although inhaled Mx does not
effect bronchovascular leakage, it does enhance airway
leakage when administered intravenously. Larrazet et
al. (21) suggested that, under the latter condition, -agonist-induced systemic hypertension caused
pulmonary congestion, which in turn resulted in airway leakage that was
unrelated to any direct effect of Mx on bronchovascular permeability.
However, increasing doses of Mx enhanced bronchovascular leakage in a
dose-dependent fashion, despite similar drug-induced changes in MAP for
each dose. The lowest dose did not effect leakage. On the
basis of these observations, Mx appears to have a direct effect on
bronchovascular permeability in rats; this effect is consistent with
our findings. In our study, neither aerosolized Mx nor NE affected HR
or MAP, suggesting that any effects attributed to
-agonists are likely to be local. However, our goal
was not to determine whether -agonists enhance
bronchovascular permeabiltiy but to determine whether these agents
inhibit HIB by decreasing bronchial blood flow and bronchovascular
leakage. Figures 4 and 5 clearly demonstrate these agents do
not.
We previously suggested that bronchovascular leakage occurs in concert
with airway narrowing and protects the bronchial mucosa from excessive
losses of heat and water (13, 14). Mucociliary clearance in asthmatic
subjects was reduced during and increased after isocapnic
hyperventilation with dry air (7). Hyperventilation with dry air does
increase bronchial blood flow in animals (2, 3, 28) and, as seen in
this study (Figs. 4 and 5) and others (10, 13, 14), results in
bronchovascular hyperpermeability. Thus the movement of extravasated
fluid into the airway lumen may account for the increased clearance
reported in these studies. -Agonists can affect
tracheobronchial blood flow (6, 20) and water transport across airway
epithelia (4) and may attenuate HIB by stimulating a fluid-replacement
mechanism. We have published similar results for furosemide (16), which
may also attenuate HIB in part by enhancing dry air-induced
bronchovascular leakage and increasing water delivery to airway
tissues. This would theoretically reduce the strength of the osmotic
stimulus produced during a DAC and diminish the magnitude of
obstruction that subsequently develops.
In summary, although Mx and NE inhibit HIB, they do not do so by
reducing dry air-induced mucosal perturbation and injury, mast cell
degranulation, or bronchovascular hyperpermeability. The observation
that -agonists increase dry air-induced mucosal injury and bronchovascular leakage supports the notion that water replacement through the bronchial circulation opposes the desiccating effect of hyperventilation with dry air. The proximal distribution of
both airway mucosal injury and bronchovascular leakage suggests that
bronchi are exposed to a greater desiccating burden than bronchioles.
Furthermore, it seems likely that the augmentation of
bronchovascular leakage observed in -agonist-treated
bronchi arises as a consequence of mucosal injury. Whether or not the tendency of these -agonists to enhance dry
air-induced microvascular leakage plays a significant physiological
role in the inhibition of HIB remains in question. However, even modest
changes in microvascular permeability may adequately compensate for
water loss that normally occurs during hyperventilation. If this is
correct, then future studies examining the effects of
-agonists and other vasoactive drugs on airway fluid
balance and water flux may provide insights into the mechanisms
underlying the development and expression of hyperpnea-induced asthma.
However, it is important to note that these drugs do enhance
hyperventilation-induced airway injury and as such appear to be
unlikely candidates for long-term clinical application.
ACKNOWLEDGEMENTS
We thank Dr. Walter Ehrlich for providing critical review of an early draft of this manuscript, and we gratefully acknowledge the superb technical assistance of Judith Corum and Dick Rabold.
FOOTNOTES
Address for reprint requests: A. N. Freed, Div. of Physiology; 7006 Hygiene, The Johns Hopkins Univ., 615 North Wolfe St., Baltimore, MD 21205 (E-mail: afreed{at}jhsph.edu).
Received 13 March 1997; accepted in final form 11 August 1997.
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