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1-proteinase inhibitor blocks
antigen- and mediator-induced airway responses in sheep
Division of Pulmonary and Critical Care Medicine, University of Miami at Mount Sinai Medical Center, Miami Beach, Florida 33140
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1-Proteinase inhibitor
(1-PI) is a natural serine protease
inhibitor. Although mainly thought to protect the airways from neutrophil elastase, 1-PI may also regulate the
development of airway hyperresponsiveness (AHR), as indicated by our
previous findings of an inverse relationship between lung
1-PI activity and the severity of antigen-induced
AHR. Because allergic stimulation of the airways causes release
of elastase, tissue kallikrein, and reactive oxygen species (ROS), all
of which can reduce 1-PI activity and contribute to AHR,
we hypothesized that administration of exogenous 1-PI
should protect against pathophysiological airway responses caused by
these agents. In untreated allergic sheep, airway challenge with
elastase, xanthine/xanthine oxidase (which generates ROS),
high-molecular-weight kininogen, the substrate for tissue kallikrein,
and antigen resulted in bronchoconstriction. ROS and antigen also
induced AHR to inhaled carbachol. Treatment with 10 mg of recombinant
1-PI (r1-PI) blocked the
bronchoconstriction caused by elastase, high-molecular-weight
kininogen, and ROS, and the AHR induced by ROS and antigen. One
milligram of r1-PI was ineffective. These are the first
in vivo data demonstrating the effects of r1-PI. Our
results are consistent with and extend findings obtained with human
plasma-derived 1-PI and suggest that 1-PI
may be important in the regulation of airway responsiveness.
proteases; oxygen radicals
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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AIRWAY HYPERRESPONSIVENESS (AHR) is an important feature of asthma that not only constitutes a qualitative diagnostic feature of the disease but also relates quantitatively to its clinical manifestations and to the response to therapy (31). Allergen challenge or acute asthma exacerbations can induce a further transient increase in AHR in asthmatic subjects. Although the exact mechanisms responsible are not fully understood, the recruitment of neutrophils and eosinophils to the airways and the subsequent release of inflammatory mediators, including proteases, lipid mediators, and reactive oxygen species (ROS), are thought to contribute to the pathophysiology of allergen-induced AHR (12, 15, 16, 32).
Observations in asthma patients, as well as our own previous studies, suggest that two serine proteases, tissue kallikrein (TK) and neutrophil elastase (NE), may be of special importance and could act in concert with regard to the development of AHR. TK is localized in serous cells of submucosal glands in the airways (19, 20). TK can be released from these cells by various stimuli, including NE (8, 21) and ROS (7). TK is also expressed and released by neutrophils (33). Its primary action is to cleave low- and high-molecular-weight kininogen (HMWK) to form the potent spasmogenic peptide lysyl-bradykinin. Increased TK has been found in airway secretions after acute exacerbations and/or in bronchoalveolar lavage fluid (BALF) after allergen challenge in asthmatic patients (5). Increases in these same mediators were found in BALF of allergic sheep after antigen challenge (17). In the latter study, the increases in BALF TK were most prevalent at the time the animals had developed antigen-induced AHR, suggesting that the actions of TK contributed to the AHR (17).
The relationship between TK and NE is supported by studies showing that aerosolized NE causes bronchoconstriction and AHR in guinea pigs (23) and that aerosolized porcine pancreatic elastase (PPE) causes bronchoconstriction in sheep (21). In the sheep study, the PPE-induced response was mediated by an increase in TK activity and was associated with increased levels of kinins (21). The increases in bronchial tone after airway challenge with elastase in these animal models are consistent with observations made in patients, where increased levels of active and total elastase were found in induced sputum of asthmatic patients and the levels were inversely correlated with the patients' degree of airway obstruction (27).
Given that 1) NE and ROS cause increases in TK activity in
the airways, 2) the neutrophil itself is a source of TK, and
3) increased TK activity may be involved in heightened
airway responses, then understanding factors that control these
increases in TK activity would be important. In studies in which
upregulation of TK and/or NE was associated with abnormal airway
responsiveness, we observed a decrease in the activity of
1-proteinase inhibitor (1-PI) (6,
7). 1-PI is a 52-kDa serine protease inhibitor with a broad spectrum of action in the lower respiratory tract. Its
major function is to inhibit NE, providing >90% of the anti-NE protective action (1, 26, 29). In the studies examining the role of TK in antigen-induced AHR, we observed that
1-PI activity was inversely correlated with the increase
in BALF TK activity (6). These observations suggest a
possible regulatory role of 1-PI in this regard.
Similarly, in the asthmatic patients whose sputum contained increased
levels of total and active elastase, there were increased levels of
1-PI, but the activity of this proteinase inhibitor was
insufficient to counteract the increase in elastase, because the
analysis showed that increased levels of active elastase persisted and
resulted in airway obstruction (27).
Collectively, these data would suggest that, under normal conditions,
1-PI acts to control NE and TK activity in the airways, but, during periods of active inflammation, the protease-antiprotease imbalance is shifted in favor of the proteases, allowing TK activity to
increase and resulting in abnormal airway responsiveness. The fact that
increased levels of 1-PI cannot counteract the increased protease load could result not only from an excess of active proteases in the lung but also from its inactivation by ROS and proteases (4, 18, 24, 28). If, however, factors that reduce
1-PI activity can result in abnormal airway function,
then supplemental 1-PI should reverse this process. Our
laboratory's previous studies, showing that exogenously administered
natural 1-PI (human 1-PI; Prolastin) was
able to reduce the antigen-induced AHR and the concomitant increase in
BALF TK activity in allergic sheep support this contention
(6).
These experimental data suggest a beneficial role of
1-PI in maintaining normal airway function. The only
commercially available source, however, is the human plasma-derived
product (Prolastin). Availability of source of the material and risks
associated with human-derived components could restrict its use in
hyperactive airway disease. Recently, a recombinant form of
1-PI (r1-PI) has become available. This
r1-PI is expressed in yeast, and, in preliminary
reports, the protein appears equipotent to the natural protein
(14). In this study then, we tested the hypothesis that
r1-PI would block antigen-induced AHR at doses
comparable with the natural inhibitor. In addition, we extended our
studies to show that r1-PI is effective against airway
challenges with PPE, ROS, and HMWK, agents that would affect the
inhibitor's activity in vivo. Our findings supported our hypothesis
and, furthermore, provide the first in vivo data that this
r1-PI is effective against antigen and specific mediator
challenges that reduce lung antiprotease activity.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A total of 22 sheep (mean weight: 30.8 kg) were used for this study. All animals had a history of airway hypersensitivity to Ascaris suum antigen. The study was conducted at Mount Sinai Medical Center under the approval of the Mount Sinai Medical Center Animal Research Committee.
Airway Mechanics
To study airway mechanics, the animals were restrained in a cart, in an upright position, with their heads immobilized. A balloon catheter was advanced through one nostril into the lower esophagus after topical anesthesia with 2% lidocaine solution. The animals were intubated with a cuffed endotracheal tube through the other nostril by using a flexible fiber-optic bronchoscope. Pleural pressure was measured via an esophageal catheter (filled with 1 ml of air) that was positioned 5-10 cm from the gastroesophageal junction. In this position, the end-expiratory pleural pressure ranged between
2 and
5 cmH2O. Lateral pressure in the trachea was measured
with a side-hole catheter (inner dimension 2.5 mm) advanced through and
positioned distal to the tip of the endotracheal tube. Transpulmonary
pressure, the difference between tracheal and pleural pressure, was
measured with a differential pressure transducer catheter system. For
the measurement of pulmonary resistance (RL), the proximal
end of the endotracheal tube was connected to a pneumotachograph
(Fleisch; Dyna Sciences, Blue Bell, PA). The signals of flow and
transpulmonary pressure were recorded on an oscilloscope recorder,
which was linked to a computer for on-line calculation of
RL. Respiratory volume was obtained by digital integration
of the flow signal and was used, together with transpulmonary pressure
and flow, at isovolumetric points to derive RL
(30), as previously described by us (6).
Analysis of 5-10 breaths was used for determination of
RL.
Aerosols
A disposable medical nebulizer (Raindrop; Nelcor Puritan Bennett, Carlsbad, CA) was used to generate all aerosols. The output from the nebulizer generated an aerosol with mass median aerodynamic diameter of 3.2 µm (geometric SD 1.9), as determined by an Andersen cascade impactor, and was directed into a plastic T piece, which was interconnected to the inspiratory port of a Harvard piston ventilator (Harvard Apparatus, Natick, MA) with the animal's tracheal tube. To control aerosol delivery, a dosimeter system, consisting of a solenoid valve and a source of compressed air (20 psi), was used. The solenoid valve was activated for 1 s at the beginning of the inspiratory cycle of the ventilator. Aerosols were delivered at a tidal volume of 500 ml and a rate of 20 breaths/min.Measurement of Airway Responsiveness
To assess airway responsiveness, we performed cumulative dose-response curves to carbachol by measuring RL immediately after inhalation of PBS (pH 7.4) and after each consecutive administration of 10 breaths of increasing concentrations of carbachol up to 4% wt/vol. The provocation test was discontinued when RL increased over 400% from the post-PBS value, or after the highest carbachol concentration had been administered. Airway responsiveness was estimated by determining the cumulative carbachol dose [in breath units (BUs)] that increased RL by 400% over the post-PBS value (PC400), by interpolation from the dose-response curve. One BU was defined as one breath of an aerosol solution containing 1% wt/vol carbachol.Agents
A. suum was purchased from Greer Diagnostics (Lenoir, NC) and dissolved in PBS at a concentration of 82,000 protein nitrogen U/ml and delivered as an aerosol (20 breaths/min × 20 min). r1-PI was a gift from Alpha One Pharmaceuticals
(Alameda, CA). It was dissolved in sterile distilled water and given as
an aerosol (10 mg/3 ml or 1 mg/3 ml). HMWK from human plasma was
purchased from Calbiochem-Novabiochem (La Jolla, CA), dissolved in PBS
(100 µg/3 ml), and delivered as an aerosol. Xanthine (X) and xanthine
oxidase (XO) from buttermilk were purchased from Sigma Chemical (St.
Louis, MO), dissolved in PBS to a 0.1% solution and 4.1 U/2 ml, and
delivered as aerosols. PPE was purchased from Sigma Chemical, dissolved in PBS, and given as an aerosol. All concentrations of agents used in
the present studies were selected based on previous work by our group
(6, 13, 21).
Bronchoalveolar Lavage for TK Analysis
The distal tip of a specially designed 80-cm fiber-optic bronchoscope was wedged into a randomly selected subsegmental bronchus. Lung lavage was performed by slow infusion and gentle aspiration of 60 ml of PBS (at 37°C) in two different airway segments (30 ml each) by using a 30-ml syringe attached to the working channel of the instrument. The effluent was filtered through a double layer of gauze and placed in a tube. All tubes were immediately placed on ice and then centrifuged at 250 g at 4°C for 15 min. The supernatant was recentrifuged at 3,000 g at 4°C for 15 min, saved, and frozen for subsequent analysis.Before mediator analysis, BALF supernatant was thawed and recentrifuged at 12,500 g at 4°C for 15 min. Unconcentrated BALF was analyzed for TK activity by cleavage of DL Val-Leu-Arg pNA, as described by our laboratory previously (6). Values were expressed in arbitrary units (1 unit = change in optical density at 405 nm in 24 h).
Protocols
Effects of r1-PI on antigen-induced AHR.
CONTROL TRIAL.
In six sheep, PC400 values were measured 1-3 days
before antigen challenge. On the day of the experiment, RL
was measured, and then the animals were given A. suum
antigen. RL was then measured immediately after
challenge, hourly from 1 to 6 h after challenge, and then one-half
hourly from 6.5 to 8 h after challenge. On the next day the
postchallenge PC400 was determined.
1-PI at either 10 or 1 mg was given 30 min before antigen challenge.
POSTTREATMENT TRIAL.
In four sheep, the same protocol was repeated, except that aerosolized
r1-PI at either 10 or 1 mg was given 24 h after
antigen challenge, 30 min before determining the postchallenge
PC400.
All experiments were performed by using a randomized crossover design
and were separated by at least 3 wk.
Effects of r1-PI on TK activity in BALF.
In five sheep, TK activity in BALF was measured at baseline and 24 h after antigen challenge with A. suum. The same protocol was repeated after treating the animals with aerosolized
r1-PI (10 mg) either 30 min before or 24 h after
antigen challenge.
Effects of r1-PI on HMWK-induced airway responses.
To confirm that the effect of r1-PI resulted, in part,
from its interaction with TK, we measured the airway response to
inhaled HMWK, a substrate for TK (6), in the presence and
absence of r1-PI (10 mg). In five animals,
RL was measured before and then immediately, 15, 30, and 60 min after HMWK challenge (100 µg/3 ml). For these studies, the sheep
were treated with either placebo (PBS) or aerosolized
r1-PI (10 mg) 30 min before HMWK challenge. All
experiments were performed according to a randomized crossover design
and were separated by at least 72 h.
Effects of r1-PI on PPE-induced airway responses.
To study the effects of aerosolized r1-PI on PPE-induced
airway bronchoconstriction, five sheep were challenged with inhaled PPE
(500 µg) before and 30 min after pretreatment with either placebo
(PBS) or aerosolized r1-PI (10 mg). RL was
measured in the baseline condition and then immediately, 5, 10, 15, and
30 min after challenge.
Effects of r1-PI on ROS-induced airway responses.
X-XO CHALLENGE.
1-PI at either 10 or 1 mg was given 30 min before X-XO challenge.
All experiments were performed in a randomized crossover design fashion
and were separated by at least 1 wk.
Statistics.
All data were analyzed by using a multivariate ANOVA for repeated
measures followed by post hoc t-test with Bonferroni
correction to identify significant pairs. Individual comparisons were
made by using paired and unpaired t-test when appropriate
(Sigmastat 2.0 for Windows, SPSS, Chicago, IL) (11).
Values in the text, Figs. 1-8, and Tables 1-3 are presented
as means ± SE; P < 0.05 was considered
significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects of r1-PI on Antigen-induced AHR and
BALF TK
1-PI (1 and 10 mg) given 30 min
before antigen challenge had no effect on these antigen-induced
constrictor responses (6). Similarly, there were no
differences in the early and late bronchial responses when
r1-PI (1 and 10 mg) was given 30 min before the
postchallenge PC400 (Fig. 1).
Before antigen challenge, there was no difference in the baseline
PC400 among all trials (Table 1). In the control group,
antigen challenge caused the PC400 to fall significantly from 23 ± 3 to 9 ± 2 BU (P < 0.001),
indicating that the animals had developed AHR. Treatment with
aerosolized r1-PI (10 mg), either 30 min or 24 h
after antigen challenge, completely blocked the antigen-induced AHR
(P < 0.001). In the low-dose protocol, r1-PI (1 mg) given either 30 min or 24 h after
challenge had no effect on any of the measured endpoints (Figs. 2 and
3).
Consistent with the physiological data, TK activity in BALF increased
5.7-fold 24 h after antigen challenge in control animals (P < 0.001). Aerosolized r1-PI (10 mg),
given either 30 min before or 24 h after challenge, resulted in
only a 2.1- and 3.1-fold increase in BALF TK activity, respectively
(P < 0.01; Fig. 4).
Effects of r1-PI on TK-mediated
Bronchoconstriction
1-PI acts in a fashion
similar to the natural protein, it should block the bronchoconstriction to inhaled HMWK. Figure 5 and Table
2 demonstrate that pretreatment with
inhaled r1-PI (10 mg) given 30 min before inhalation
challenge with HMWK completely blocks the increase in RL
(P < 0.001) seen when the animals are untreated.
Effects of r1-PI on ROS-induced Airway Responses
1-PI (10 mg) 30 min before challenge
blocked the X-XO-induced bronchoconstriction (RL increased
by 7 ± 10% over baseline; P < 0.01 vs.
control), and the PC400 values before and after challenge were 27 ± 3 and 25 ± 2 BU, respectively (Figs.
6 and 7, Table 3).
Pretreatment with aerosolized r1-PI (1 mg) was
ineffective against the X-XO-induced bronchoconstriction and AHR (Figs.
6 and 7, Table 3).
Effects of r1-PI on PPE-induced Bronchoconstriction
1-PI (10 mg) 30 min before challenge completely blocked
this response (Fig. 8 and Table 2).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of this study show that, in the allergic sheep model,
r1-PI blocked the airway responses induced by antigen, HMWK, ROS, and PPE. These are the first in vivo data showing the protective effects of this r1-PI on airway challenges
that are targeted to increased lung protease levels.
The rationale for the present study was based on previous findings from
this laboratory. In allergic sheep, antigen challenge causes AHR, and
this mechanism is associated with increased TK activity and decreased
1-PI activity in BALF (6). The blockade of
these events with exogenous 1-PI suggested that
1-PI may be important in the regulation of these
responses. The protection required active protein, because the
protective effects were lost if the 1-PI was denatured
(6). The requirement for active enzyme, and the data
obtained in both the previous and present study, rule out the potential
for nonspecific protective effects of the protein. To further support
the contention that the regulation of TK was important, we challenged
the animals with HMWK, the substrate for TK. In the presence of active
TK, HMWK is cleaved to form lysyl-bradykinin and subsequently
bradykinin, which cause bronchoconstriction in these animals. Active,
but not denatured, 1-PI blocked this response. The
results of the present investigation confirm the actions of
r1-PI on these challenges. Inhaled r1-PI (10 mg), given either 30 min or 24 h after allergen challenge, blocked the antigen-induced AHR and the concomitant increase in BALF TK
activity. Consistent with this finding was blockade of HMWK-induced bronchoconstriction.
Allergic stimulation of the airways is associated with the release of
several mediators, including NE and ROS, that can contribute to a loss
of 1-PI activity. Endogenous and exogenous ROS oxidize the reactive site of 1-PI, leading to substantial
reduction of its activity, whereas proteases originating from
inflammatory cells cleave reactive site loops of 1-PI,
thereby abolishing its inhibitory activity (4, 18, 24,
28). The decreased activity of 1-PI resulting
from this combination of events would, in turn, lead to an imbalance in
the 1-PI-TK equilibrium, favoring an increase in
TK-mediated airway events. Such effects should, therefore, be
counteracted by the addition of exogenous 1-PI.
On the basis of the previous arguments, it was expected that
r1-PI would be effective in blocking the
bronchoconstrictor effects of PPE. As with antigen challenge,
PPE-induced responses in the airways are mediated by an increase in BAL
TK activity and the generation of kinins (21). Our
findings show that r1-PI has a similar pharmacological
and mechanistic profile as we observed in our previous studies with the
natural protein. It is important to note that PPE is an
acceptable alternative to NE for these types of experiments, as already
reported by us (21). Finally, we showed that aerosolized
r1-PI (10 mg) blocks both the bronchoconstriction and
the AHR induced by inhalation of X-XO, a model used to mimic generation
of ROS (13). Collectively, these data show, for the first
time, that r1-PI can modify abnormal airway responses
induced by challenges designed to increase the protease levels in the airways.
The amounts of clinical data, although limited, strongly support these
experimental observations. Christiansen and coworkers (2,
3) demonstrated the presence of TK activity in the BALF of
asthmatic subjects and that this activity was elevated after endobronchial challenge with allergen. In addition, Gaillard and coworkers (10) showed the presence of a functional
deficiency of the 1-PI in asthmatic subjects, which
could be important in the pathogenesis of the inflammatory processes
characterizing asthma, and Vignola et al. (27) showed that
a relative decrease in 1-PI activity, resulting in
increased levels of active elastase in sputum from asthmatic subjects,
was associated with bronchoconstriction. In a selected group of
patients, an association between a defective 1-PI
phenotype and AHR has been demonstrated (22, 25). Finally, in a small group of patients, 1 wk of 1-PI treatment was
shown to reduce baseline airway responsiveness (9).
In summary, our findings are consistent with those previously obtained
with Prolastin in this animal model. More importantly, they add novel
observations about the efficacy of r1-PI in blocking HMWK-, ROS-, and PPE-induced changes in airway function. Collectively, these results suggest a potential common mechanism by which the release
of ROS and proteases after antigen challenge may lead to AHR. Finally,
the fact that an r1-PI has potential therapeutic effects
is important because the recombinant protein, unlike the natural
protein whose supply is limited because of the demand by patients with
inherited 1-PI deficiency, would be available in
unlimited quantities. Furthermore, the r1-PI would not
be associated with the potential risk of transmitting a blood-borne disease.
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ACKNOWLEDGEMENTS |
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This study was supported in part by Arriva Pharmaceuticals.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Scuri, Dept. of Research, Mount Sinai Medical Center, 4300 Alton Rd., Miami Beach, FL 33140 (E-mail: mscuri{at}MSMC.com).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/japplphysiol.00400.2002
Received 7 May 2002; accepted in final form 1 August 2002.
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TOP
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METHODS
RESULTS
DISCUSSION
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