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Department of Environmental Health Sciences, The Johns Hopkins University, Baltimore, Maryland 21205; and The 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. Effect of furosemide on hyperpnea-induced airway obstruction, injury, and microvascular leakage. J. Appl. Physiol. 81(6): 2461-2467, 1996.
Furosemide
attenuates hyperpnea-induced airway obstruction (HIAO) in asthmatic
subjects via unknown mechanism(s). We studied the effect of furosemide
on dry air-induced bronchoconstriction, mucosal injury, and
bronchovascular hyperpermeability in a canine model of exercise-induced
asthma. Peripheral airway resistance (Rp) was recorded before and after
a 2-min dry-air challenge (DAC) at 2,000 ml/min. After pretreatment
with aerosolized saline containing 0.75% dimethyl sulfoxide, DAC
increased Rp 72 ± 11% (SE, n = 7) above baseline; aerosolized furosemide
(10
3 M) reduced this
response by ~50 ± 6% (P < 0.01). To assess bronchovascular permeability, colloidal carbon was
injected (1 ml/kg iv) 1 min before DAC, and after 1 h, the vehicle- and
furosemide-treated airways were prepared for morphometric analysis.
Light microscopy confirmed previous studies showing that DAC damaged
the airway epithelium and enhanced bronchovascular permeability.
Furosemide did not inhibit dry air-induced mucosal injury or
bronchovascular hyperpermeability and in fact tended to increase airway
damage and vascular leakage. This positive trend toward enhanced
bronchovascular permeability in DAC canine peripheral airways is
consistent with the hypothesis that furosemide inhibits HIAO in part by
enhancing microvascular leakage and thus counterbalancing the
evaporative water loss that occurs during hyperpnea.
asthma; bronchovascular permeability; goblet cells; hyperpnea-induced bronchoconstriction; mast cells
INTRODUCTION INHALED FUROSEMIDE inhibits hyperpnea- and
exercise-induced asthma in humans (4, 14, 25, 26, 29). It also
attenuates airway responsiveness to indirect stimuli such as aspirin
(31), distilled water (18), hypertonic saline (27), and metabisulfite (19). Central and peripheral airways appear to be equally protected (29). Although the site and mechanism of the effect of inhaled furosemide are not well understood, its mechanism of action has been
variously attributed to the inhibition of airway sensory nerves (32),
mast cell mediator release (18), bronchoconstricting prostaglandins
(16), to the stimulation of bronchorelaxing prostanoids (25), or to
local vasodilation (14). It is generally agreed that the
interruption of epithelial cell
Na+-Cl The attenuation of hyperpnea-induced airway obstruction (HIAO) in
asthmatic subjects by furosemide is associated with concomitant reductions in airway cooling and rewarming (14). Inhaled furosemide could thus dilate the tracheobronchial vasculature, enhance heat delivery, and thereby reduce the thermal effects associated with hyperpnea. Although furosemide relaxes aorta and pulmonary artery rings
in vitro (1), it fails to affect a sodium metabisulfite-induced increase in bronchial blood velocity in sheep (20). Thus furosemide does not appear to alter tracheobronchial blood flow. However, HIAO and
injury are accompanied by an increase in bronchovascular permeability
and extravasation of fluid into the airway wall (9, 10). As suggested
by Rodwell et al. (26), furosemide may enhance dry air-induced
bronchovascular leakage and attenuate HIAO by increasing paracellular
water movement in response to an osmotic stimulus.
We designed the present study to address this basic hypothesis. In so
doing, we first determined that furosemide inhibits HIAO in a canine
model of exercise-induced asthma. We then documented the effect of
furosemide on dry air-induced mucosal injury and bronchovascular
hyperpermeability in peripheral airways.
METHODS Experimental Techniques
and
Na+-K+-2Cl
cotransport consequent to furosemide's being a loop diuretic is
unlikely to account for its inhibitory action (6). However, furosemide
may attenuate bronchoconstriction by reducing apical chloride channel
activity in airway epithelia (2).
1 · min1.
Dry-air challenge (DAC).
Insufflation of dry 5% CO2 in air
was increased from 200 to 1,500-2,000 ml/min for 2 min. At the end
of 2 min, it was reduced to the baseline flow rate of 200 ml/min.
Administration of furosemide aerosol.
Either furosemide [Sigma Chemical, St. Louis, MO,
103 M in 0.9% saline with
0.75% dimethyl sulfoxide (DMSO); 366 ± 3 mmol/kg, n = 3] or 0.75% DMSO-saline (381 ± 4 mmol/kg, n = 3)
aerosols were generated with the use of an ultrasonic nebulizer
(Ultra-Neb 100, DeVilbiss, Somerset, PA) that delivered ~ 15 µl/min. The catheter was temporarily removed, and the aerosol was
generated in air with 5% CO2 and
was delivered for 2 min into the wedged segment at 200 ml/min via the
suction port of the bronchoscope. Thus ~0.01 mg of furosemide was
delivered to each sublobar segment. Rp was recorded after the
administration of furosemide, and DAC was done immediately after a
stable baseline Rp was reestablished.
Tissue removal and preparation.
Dogs were exsanguinated, a median sternotomy was done, the pulmonary
artery and left atrium were cannulated, and the pulmonary vasculature
was perfused with Hanks' buffered salt solution. The lungs were
removed within 30-60 min after DAC and were prepared for
morphometric analysis as follows. After each lobe was cannulated, Streck tissue fixative (Streck Laboratories, Omaha, NE) was instilled into each lobe to an inflation pressure of 20 cmH2O. Lobes were then immersed in
the fixative for 24-48 h before dissection. After fixation, the
parenchyma was dissected free from the bronchi, and the location of the
bronchoscope was determined via an airway map that was constructed at
the beginning of the experiment. The airway tree was photocopied,
diagrammed, and cut serially into ~3-mm- long rings and labeled for
image analysis. A continuous ethanol series was used to dehydrate the
bronchial rings, which were embedded in glycolmethyacrylate with the
use of a JB-4 embedding kit (Polysciences, Warrington, PA). One 2- to
3-mm cross section of each airway ring was stained with periodic
acid-Schiff (PAS) and one with toluidine blue (TB) and naphthol yellow
S.
Morphometric analysis.
Airways with cross sections ranging from 0.5 to 4.4 mm in diameter were
examined, using light microscopy and an image-analysis system (Sigma
Scan, Jandel Scientific, Corte Madera, CA). Airways 
4.5 mm in
diameter were excluded due to their proximity to the bronchoscope (~5 mm in diameter). Control airways were unwedged sublobar segments that were not exposed to DAC, but were located adjacent to a wedged segment. All cross sections were categorized as
either bronchi (cartilaginous airways) or bronchioles (noncartilaginous airways). The relative condition of the airway mucosa was categorized as either C + G (presence of ciliated and goblet cells), C 
G (containing cells with either very few or no goblet cells) or damaged
mucosa (containing either squamous or basal epithelia or exposed
basement membrane) (10). The mucosal categories C + G and C G
were considered normal. The perimeter of the basement membrane
(PBM)
and the lengths of normal and damaged mucosa were measured.
PBM
was used to calculate the maximally relaxed bronchial diameter
(B)
(D = PBM/B).
Three to eight airway cross sections were evaluated from each
experimental sublobar segment, and two airway cross sections were
examined from each control segment. The following measurements were
obtained 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 normal 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 number of mast cells in the lamina propria and submucosa
of the airway wall located directly below either normal or damaged
mucosa was counted in cross sections stained with TB. Mast cells were
identified as cells that had granules stained with TB. The number of
mast cells was expressed per square millimeter of lamina propria or
submucosa located below either normal or damaged mucosa. The
permeability of vessels in the lamina propria and submucosa located
below normal and damaged epithelium was estimated by measuring the area
of the vascular wall occupied by colloidal carbon in each airway cross
section stained with PAS. Bronchovascular leakage, as indicated by
extravasation of colloidal carbon, was expressed as square micrometers
per square millimeters of airway tissue (10, 24).
Experimental Protocols
Effects of furosemide on dry air-induced bronchoconstriction. Six dogs (7 lobes; mass = 22.6 ± 1 kg) were initially anesthetized with sodium thiopental (25 mg/kg), followed by a continuous thiopental infusion (4-6 mg · kg1 · h1)
and supplemented with intravenous fentanyl citrate (25-50 µg) given every 15-30 min. DAC was done after establishment of a
stable baseline Rp, and Rp was recorded at 0.5, 2, 5, 10, and 15 min after the first DAC. After Rp returned to baseline, furosemide was
aerosolized into the wedged sublobar segment, baseline Rp was recorded,
and the DAC was repeated. One lobe was exposed to a 1,500 ml/min DAC,
and six lobes were exposed to a 2,000 ml/min DAC for 2 min.
Four dogs [5 lobes; mass = 20.5 ± 2 kg (SE)] were pretreated with
the vehicle aerosol, and DAC was done as described above. Two lobes
were exposed to a 1,500 ml/min DAC, and three lobes were exposed to a
2,000 ml/min DAC for 2 min.
Dry air-induced changes in airway morphology.
Five dogs (10 lobes; 17.6 ± 1 kg) were anesthetized with
pentobarbital sodium (30 mg/kg) and supplemented with 30 mg of this drug every 30-60 min. In each dog, DAC was performed in one
sublobar segment ~15 min after pretreatment with aerosolized vehicle
and in another sublobar segment ~15 min after pretreatment with
aerosolized furosemide. Baseline Rp was recorded after aerosol
delivery, and colloidal carbon (1 ml/kg) was injected into the femoral
vein ~2 min after DAC was done in each sublobar segment. Dogs were exsanguinated 15 min after DAC.
Statistical Analyses
Rp data were analyzed with the use of a repeated-measures analysis of variance (ANOVA) and Duncan's multiple-range test. All morphometric data were evaluated using either a Student's t-test, Mann-Whitney U-test, or the Kruskal-Wallis one-way ANOVA for comparison of treatment means. Nonparametric multiple comparisons were done based on the Newman-Keuls test by using rank sums instead of means to compare any two treatments. All values were expressed as means ± SE. Statistical significance was judged at P < 0.05.RESULTS
Effects of Vehicle on HIAO
Mean baseline resistances preceding the first and second DAC were 0.76 ± 0.3 and 0.78 ± 0.3 cmH2O · ml1 · s
(n = 5), respectively, and were not
significantly different (Fig.
1A).
The first and second DAC increased Rp by 69 ± 7 and 65 ± 10%
over baseline, respectively. The average Rp recorded at each time point
after each challenge was similar.
Effects of Furosemide on HIAO
Mean baseline Rp preceding each of the two DAC was similar (0.95 ± 0.2 and 0.98 ± 0.2 cmH2O · ml1 · s;
Fig 1B). The first DAC increased Rp
by 72 ± 1%. In contrast, after treatment with furosemide, DAC
increased Rp by only 34 ± 5%. Dry air-induced changes in Rp were
significantly attenuated at 2 (P < 0.01) and 5 min (P < 0.01)
postchallenge when compared with similar points in time after the first
DAC.
Morphometric Analysis of DAC Airways
A total of 88 airway cross sections from five dogs were examined. The average diameter of bronchi and bronchioles was 3.5 ± 0.13 (n = 35) and 1.77 ± 0.11 mm (n = 53), respectively. Hyperpnea-induced mucosal injury. The perimeter of control bronchi and bronchioles was quantified in terms of the percentage of C + G, C G, and damaged mucosa (Table 1). Control bronchi had 1 ± 1%,
whereas control bronchioles had 2 ± 2% damaged mucosa. DAC
significantly increased the proportion of damaged mucosa in
vehicle-treated DAC bronchi (P < 0.01) but did not do so in the bronchioles of that group. Similarly,
the furosemide-treated DAC bronchi contained 34 ± 18% damaged
mucosa (P < 0.05) compared with
control bronchi, whereas their bronchioles did not show significant
damage (Fig. 2). There was no significant drug effect.
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Dry air-induced changes in goblet cell number. The number of ciliated cells per millimeter of basement membrane in unchallenged control, DAC vehicle-treated, and DAC furosemide-treated bronchi were similar (Table 1). The number of goblet cells per millimeter of basement membrane was also similar for bronchi in the three groups. The bronchioles in the three groups showed the same trend with similar numbers of ciliated cells per millimeter of basement membrane and comparable numbers of goblet cells per millimeter of basement membrane (Table 1). As seen in Fig. 3, although not significant, DAC tended to decrease G/C ratios.
Dry air-induced changes in mast cell number. Regardless of mucosal condition (Fig. 4), the distribution of mast cells in the lamina propria of the control, vehicle-treated, and furosemide-treated bronchi and bronchioles was similar (Table 1). No differences were detected in the number of submucosal mast cells in either bronchi or bronchioles. Mast cell number per square millimeter of lamina propria located below C + G and C
G mucosa was similar and was combined for analysis
under the rubric of normal mucosa. Mast cell number per square
millimeter of lamina propria was then expressed as a function of
mucosal condition (normal vs. damaged) regardless of airway size (Fig. 5). The number of mast cells located below
normal ciliated mucosa in control airways was 255 ± 21/mm2 and was not affected by DAC
in either vehicle-treated (195 ± 25/mm2,
P = 0.19) or furosemide-treated (182 ± 24/mm2,
P = 0.11) airways. In contrast, the
number of mast cells located below damaged mucosa in the
furosemide-treated DAC exposed airways was significantly reduced (69 ± 21/mm2,
P = 0.016) compared with unexposed
control airways. Mast cell numbers also tended to be lower in
vehicle-treated airways compared with control
(P = 0.114).
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 and submucosa of control bronchi and bronchioles (Fig. 6). The density of colloidal carbon increased from 1-2 to 11 ± 4.9 and 22 ± 13.6 µm2/10
2
mm2
(P < 0.05) in DAC-exposed bronchi
pretreated with either vehicle or furosemide, respectively. No
significant difference existed between the vehicle- and
furosemide-treated airways. DAC did not alter bronchovascular leakage
in the submucosa of bronchi, nor did it significantly effect
bronchovascular permeability in bronchioles.
Dry air-induced vascular leakage in the lamina propria was also examined as a function of mucosal condition regardless of airways size (Fig. 7). The density of colloidal carbon located below normal ciliated mucosa was 1.1 ± 0.3 µm2/10
2
mm2 in control airways and was not
different from that observed in C + G mucosa of either DAC vehicle- or
furosemide-treated airways (P = 0.421). Colloidal carbon located below C G mucosa in
DAC-exposed vehicle-treated (4.2 ± 1.2 µm2/102
mm2) and furosemide-treated (2.8 ± 0.4 µm2/102
mm2) airways were significantly
increased when compared with normal mucosa in control airways
(P = 0.016). Extravasation of carbon beneath damaged mucosa was even greater: 8.9 ± 4.0 µm2/102
mm2 in vehicle-treated airways and
34.6 ± 13.5 µm2/102
mm2 in furosemide-treated airways
(P = 0.016). However, no significant difference between treatments was detected
(P >0.11).
DISCUSSION
Pretreatment with aerosolized furosemide reduces HIAO in canine
peripheral airways by ~50% compared with its vehicle control (Fig.
1). This level of inhibition compares favorably with other drugs
previously used in our canine model that have modes of action that are
better understood: methoxamine (an
1-adrenergic agonist) inhibited
HIAO by ~25% (22), atropine by ~30% (12), indomethacin by ~50%
(11, 12), noradrenaline by ~60% (22), aminophylline (33) and MK-0591
(a leukotriene biosynthesis inhibitor) (21) by ~65%, and
salbutamol by ~75-100% (23, 30). The efficacy of furosemide to
inhibit HIAO in our canine model is similar to that seen in the
inhibition of hyperpnea- and exercise-induced airway obstruction in
asthmatic subjects, which varies from 30 to 60% (4, 14, 15, 25, 26,
29).
In this study, morphometric analysis revealed that unexposed control airways were composed of normal ciliated epithelium and goblet cells, with no more than 2% of the airway mucosa appearing damaged (Fig. 2). Although DAC tended to decrease G/C ratios (an indicator of goblet cell degranulation and mucosal perturbation) in normal bronchi, this trend was nonexistent in bronchioles (Fig. 3). DAC induced significant mucosal injury only in bronchi. Approximately 21% of the perimeter of vehicle-treated bronchi were injured, whereas ~34% of the furosemide-treated perimeter was damaged after DAC (Fig. 2). The extent of mucosal injury reported here is relatively small compared with our previously published results (9, 23, 24), but this is a consequence of using a weaker stimulus [2-min rather than 5-min exposures (10)] for this study.
Furosemide did not reduce the extent of dry air-induced mucosal injury in bronchi (Fig. 3), suggesting that injury per se was not directly responsible for HIAO. However, furosemide may interfere at some point in the cascade of events that are initiated "downstream" from the site of airway injury. In contrast to furosemide, pretreatment with salbutamol significantly reduced mucosal injury even in the presence of a stronger desiccating stimulus (5-min exposure) (23). The fact that airway epithelial cells can generate inhibitory signals that decrease bronchial smooth muscle responsiveness to contractile agonists (5) is consistent with the greater protection against HIAO afforded by salbutamol (30) in comparison with furosemide. Thus these observations suggest that the magnitude of epithelial damage may indeed play an indirect role in the development of HIAO.
Unlike exposure to a 5-min DAC (9, 23, 24), challenge for 2 min did not significantly alter mast cell number in either the lamina propria or submucosa of airways of any size examined in this study (Fig. 4). Although the number of mast cells located below normal ciliated mucosa in DAC bronchi did not decrease, mast cell number was reduced in dry air-exposed damaged tissue compared with undamaged airway (Fig. 5). Because completely degranulated mast cells would not be detected by our morphometric analysis, a reduction in the number of mast cells found below damaged mucosa is interpreted as an increase in mast cell degranulation. Whether mast cell degranulation either contributes to or is a consequence of mucosal injury in this canine model remains unknown. The fact that mechanical removal of airway epithelium has been reported to disrupt mast cells (7) suggests that dry air-induced mucosal injury causes mast cell degranulation. In either event, treatment with furosemide did not affect dry air-induced mast cell degranulation in damaged regions of an airway. This is similar to the effect of salbutamol on mast cell degranulation in DAC airways (23).
Furosemide has been reported to reduce the magnitude of airway cooling and rewarming that occurs during and immediately after DAC, and, in so doing, ameliorate a thermal stimulus purported to initiate HIAO in asthmatic subjects (14). However, HIAO does not develop in canine airways when cooling and rewarming occur in the absence of hyperpnea-induced airway drying (8). The fact that canine (8) and human (17) airways respond similarly to hyperpnea suggests that abrupt changes in airway temperature are not a prerequisite for the initiation of HIAO. Thus, for this study, we focused on the potential efficacy of furosemide for counterbalancing hyperpnea-induced airway dehydration. We previously suggested that bronchovascular leakage occurs in concert with airway narrowing and protects the bronchial mucosa from excessive losses of heat and water (9). Hyperpnea with dry air does increase bronchial blood flow in dogs (3) and, as seen in this (Figs. 6 and 7) and other studies (9, 10), results in bronchovascular hyperpermeability. Theoretically, furosemide can affect blood flow (1, 14) and water flux across the mucosal epithelium (6) and may in part attenuate HIAO by stimulating a fluid-replacement mechanism. If furosemide diminishes HIAO by enhancing dry air-induced bronchovascular leakage and increasing water delivery to airway tissue, it would reduce the strength of the osmotic stimulus produced during a DAC. As seen in Fig. 6, a 2-min 1,500-2,000 ml/min DAC does increase bronchovascular fluid extravasation in canine bronchi. Although there is a tendency for greater bronchovascular leakage in furosemide-treated airways, this trend is not statistically significant. Thus furosemide's mechanism of action may not be related to vascular hyperpermeability.
Examination of mucosal-dependent vascular leakage reveals significantly
greater fluid extravasation occurring below goblet cell depleted (C G) and damaged mucosa when compared with ciliated mucosa
replete with goblet cells (C + G). The variability and magnitude of
bronchovascular leakage is noticeably greater, albeit not statistically
significant (P = 0.11), in
furosemide-treated compared with vehicle-treated canine peripheral
airways (Fig. 7). These results stand in stark contrast to the report
that inhaled furosemide decreased metabisulfite-induced microvascular
leakage in the proximal airways of guinea pigs (28). However, the fact that furosemide inhibits bradykinin- but not adenosine-induced microvascular leakage specifically shows that the effect
of furosemide on vascular permeability is stimulus dependent (13). Thus
we are hesitant to ignore the obvious positive trend seen in Fig. 7
that clearly demonstrates that furosemide does not decrease and may
actually enhance bronchovascular permeability in DAC canine peripheral
airways.
In summary, we have shown that furosemide inhibits HIAO in canine peripheral airways with an efficacy similar to that reported for human asthmatic subjects. Although furosemide inhibits HIAO, it does not do so by dry air-induced mucosal injury or mast cell degranulation. Whether or not the tendency of furosemide to enhance dry air-induced bronchovascular fluid extravasation plays a significant physiological role in the inhibition of HIAO remains in question. However, even modest changes in microvascular permeability may be sufficient to compensate for the water loss that normally accompanies hyperpnea. Thus the trend toward increasing microvascular leakage is consistent with the hypothesis that furosemide enhances dry air-induced bronchovascular leakage and attenuates HIAO by increasing paracellular water movement in response to an osmotic stimulus. Experiments examining changes in airway lining fluid osmolality in vehicle- and furosemide-treated bronchi immediately after hyperpnea with dry air may provide data that would unambiguously address this hypothesis and provide further insight into the mechanisms underlying the development and expression of hyperpnea-induced asthma.
ACKNOWLEDGEMENTS
The authors thank Judith Corum and Dick Rabold for their superb technical assistance.
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}phnet.sph.jhu.edu).
Received 29 April 1996; accepted in final form 26 July 1996.
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