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We previously showed that inhaled porcine pancreatic elastase (PPE) causes bronchoconstriction in sheep via a bradykinin-mediated mechanism. Hyaluronic acid (HA), in vitro, binds and inactivates airway tissue kallikrein (TK), the enzyme responsible for kinin generation. Therefore, we hypothesized that in vivo, HA should prevent PPE-induced bronchoconstriction by binding and inactivating TK. To test this, we measured pulmonary resistance (RL) in allergic sheep before and after inhalation of PPE alone (500 µg) and after pretreatment with either inhaled HA at 70 kD, designated low molecular weight (LMW)-HA or 200 kD, designated high molecular weight (HMW)-HA at different concentrations. Inhaled PPE increased RL 147 ± 8% over baseline values and this effect was associated with a 111 ± 28% increase in bronchoalveolar lavage fluid (BALF) TK activity. HA blocked the PPE-induced bronchoconstriction and the increase in BALF TK activity in a dose- dependent and molecular weight-dependent fashion. HA alone had no effect on RL. Instillation of PPE in the lung increased kinin concentrations in BALF, a result consistent with the PPE-induced increase in BALF TK activity. Our findings show that HA blocks PPE-induced bronchoconstriction in a dose-dependent and molecular weight-dependent fashion by a mechanism that may, in part, be related to inhibition of TK activity and the formation of kinins.
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Keywords: pancreatic elastase; hyaluronan; polysaccharides; asthma; serine proteases; bradykinin
Tissue kallikreins (TKs) are a family of serine proteases secreted by gland cells of different organs (1). In the airways, TK is the major kininogenase (11) cleaving both high and low molecular weight kininogen to yield lysyl-bradykinin. This peptide can cause vasodilation, increased vascular permeability, and bronchoconstriction, all of which contribute to the pathophysiology of asthma. Consistent with TK's putative role in asthma are the findings of increased TK activity in human nasal lavage fluid and bronchoalveolar lavage fluid (BALF) after antigen challenge (11). Likewise, increased TK activity has been observed in BALF of allergic sheep after inhalation challenge with antigen, as well as other inflammatory stimuli such as metabisulfite, ozone, bacterial supernatants, and elastase (14). In all instances, this increased TK activity was associated with bronchoconstriction or airway hyperresponsiveness. Furthermore, the pulmonary abnormalities resulting from these irritant challenges were blocked by pretreatment with a bradykinin antagonist, indicating that the increased TK activity was associated with kinin generation. Therefore, factors that regulate TK release or activity may be important in airway pathophysiology.
We recently showed that elastase is one factor that influences TK concentrations in the airways. In vitro, we showed that both human and ovine neutrophil elastase release TK from ovine tracheal gland cells (19) and, in vivo, that aerosol challenge with porcine pancreatic elastase (PPE) causes bronchoconstriction in sheep. We also showed that this bronchoconstriction was associated with increased TK activity in BALF and that the bronchoconstrictor effect could be blocked with a bradykinin B2 antagonist (20). These data could have important clinical implications because increased elastase activity has been found in the airway fluids of animals after allergen provocation (21) and in the sputum of asthmatic patients after asthma exacerbations (22). Such an increase in elastase activity could induce TK release and contribute to TK-mediated bronchial responses through kinin generation.
Hyaluronic acid (HA), or hyaluronan, is a large linear polymer formed by a repeating disaccharide structure of glucuronic acid and N-acetylglucosamine with a molecular mass ranging from approximately 2 × 105 to 10 × 106. Hyaluronan is present in all vertebrates (23) and is abundant in virtually all biologic fluids. It is involved in multiple biologic processes, including cell-cell and cell-matrix signaling, regulation of cell migration and proliferation (23), and tumor transformation and metastasis (24, 25). In the lung, HA accumulates as part of the fibroproliferative response to injury and tissue remodeling. Many of these biologic functions are mediated by the cell surface receptors CD44 and RHAMM (receptor for HA- mediated motility), or CD168 (24). Interestingly, we found that, in vitro, HA binds to and inhibits TK activity (30).
Based on the collective findings from the aforementioned studies, we hypothesized that, in vivo, inhaled HA should inhibit the PPE-induced increases in TK activity and therefore the resulting bronchoconstriction. Furthermore, because of the repeating structure of the HA molecule, one would predict that larger molecular weight HA should contain a larger number of binding sites for TK and so the protective effects of HA should be molecular weight-dependent as well. Our findings support both these hypotheses.
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Adult ewes (mean weight, 27 ± 2 kg) allergic to Ascaris suum antigen were used for this study. The study was conducted under the approval of the Mount Sinai Medical Center Animal Research Committee.
Lung resistance (RL) was measured in intubated conscious sheep as previously described (18). Aerosols were generated using a disposable medical nebulizer (Raindrop; Puritan Bennett, Lenexa, KS) and a dosimeter system was used to control aerosol delivery as previously described (18).
PPE was purchased from Sigma Aldrich Co. (St. Louis, MO), dissolved in phosphate-buffered saline (PBS; pH 7.4) and delivered as an
aerosol (20 breaths/min). Low molecular weight HA (LMW-HA) from
pig trachea (average molecular weight approximately 70 kD) was purchased from Fluka Chemical Corp. (Milwaukee, WI). High molecular
weight HA (HMW-HA) from human umbilical cord (average molecular weight approximately 200 kD) was purchased from ICN Biomedicals, Inc. (Aurora, OH). Stock solutions were prepared in distilled
water and then diluted with PBS to achieve final concentrations for
aerosol delivery. Carbamylcholine (carbachol) was purchased from
Sigma Aldrich Co. (St. Louis, MO) and dissolved in PBS (pH 7.4) to a
stock concentration of 10
2 M.
Lung lavage was performed with a fiberoptic bronchoscope (18) and TK activity in the unconcentrated BALF supernatant was determined as previously described (18). Enzymatic activity was expressed as arbitrary units (1 Unit = change in optical density at 405 nm in 24 h). Values are expressed as percent changes over baseline. In a separate set of experiments, kinin concentrations in BALF were measured as previously described (31) using a standard ELISA method (32). Values are expressed in pg/ml. Total proteins were also measured in these samples using a standard bovine serum albumin (BSA) assay and the results are expressed as mg/ml.
Isometric contractile response of sheep tracheal smooth muscle preparations exposed to PPE and carbachol were measured. The tissue preparation and responses to the agonists were obtained according to a protocol previously described (33).
Protocol
Effect of inhaled HA on PPE-induced bronchoconstriction. Six animals were challenged with inhaled PPE (500 µg, in 3 ml PBS; pH 7.4). In the control protocol, PPE was given 30 min after placebo (PBS, 3 ml; pH 7.4). RL was measured at baseline, after PBS, then immediately after challenge, and at 5, 10, 15, and 30 min after challenge. In the treatment protocol, PPE challenge was performed 30 min after either inhaled LMW-HA (3 ml in PBS; pH 7.4) at concentrations of 0.2%, 0.1%, and 0.05%, or inhaled HMW-HA (3 ml in PBS; pH 7.4) at concentrations of 0.05%, 0.01%, and 0.005%. RL was measured at baseline, after treatment, immediately after challenge, and then at 5, 10, 15, and 30 min after PPE challenge. Each experiment was separated by at least 72 h.
Effect of HA on PPE-induced TK activity in BALF.
BALF TK activity was measured at baseline and 30 min after challenge with inhaled PPE. The same procedure was repeated after pretreatment with HMW-HA at concentrations of 0.05% and 0.005%.
Effect of PPE on kinin concentrations in BALF. BALF kinin concentrations and total proteins were measured at baseline and 5, 15, and 30 min after instillation challenge of the airways with either PPE (500 µg) or PBS (3 ml; pH 7.4).
Effect of PPE on isometric contraction of isolated tracheal rings.Four tracheal smooth muscle preparations were exposed to increasing
doses of PPE (2 µg, 20 µg, 200 µg). The PPE-induced contractile responses were expressed as a percentage of the contraction elicited by
a maximally effective concentration of carbachol (105 M, final bath concentration), which was added to the bath at the end of the experiment.
Statistics.
All airway data were analyzed using a multivariate analysis of variance (ANOVA) for repeated measures followed by post hoc t test with Bonferroni correction to identify significant pairs. Individual comparisons were made using paired and unpaired t test when appropriate (Sigmastat 2.0 for Windows; SPSS Inc., Chicago, IL). Kinin and total protein concentrations in BALF were analyzed using nonparametric statistics (Kruskall-Wallis and Mann-Whitney U test). Values are presented as mean ± SE; p < 0.05 was considered significant.
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Effect of HA on PPE-induced Bronchoconstriction
Inhaled PPE (500 µg) caused a short-lived bronchoconstriction reaching its peak immediately after challenge and resolving within 30 min. Pretreatment with aerosolized LMW-HA (0.2%) completely blocked this response (p < 0.001; n = 6). Lower doses of inhaled HA (0.1% and 0.05%) resulted in a differential protection against PPE-induced bronchoconstriction (Figure 1, Table 1). When the animals were pretreated with HMW-HA, complete protection against PPE-induced bronchoconstriction was achieved at a dose (0.05%) that was ineffective using LMW-HA (p < 0.001, n = 6). Aerosolization of lower doses of HMW-HA (0.01, 0.005%) again showed a dose-dependent effect (Figure 2, Table 1). Figure 3 summarizes the dose-dependent and molecular weight-dependent effects of HA. HA alone had no effect on RL (Table 1).
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p < 0.001 versus PPE and
LMW-HA 0.2% and 0.05%.
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Effect of HA on PPE-induced TK Activity in BALF
Consistent with the physiologic data, PPE caused a significant increase in BALF TK activity (p < 0.05; n = 8). Under control conditions, baseline TK activity was 0.11 ± 0.01 units. This increased to 0.21 ± 0.03 units 30 min after challenge (p < 0.05 versus baseline, n = 8). This increase was inhibited by pretreatment with inhaled HMW-HA 0.05% (baseline units = 0.13 ± 0.01 and 30 min after challenge units = 0.15 ± 0.02; p = not significant [NS]; n = 8), whereas inhaled HMW-HA 0.005% was ineffective (baseline units = 0.10 ± 0.02 and 30 min after challenge units = 0.18 ± 0.04; p < 0.05; n = 7) (Figure 4).
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Effect of PPE on Kinin and Total Protein Levels in BALF
Figure 5 illustrates the effect of PPE instillation on lung kinin concentrations (A) and on total protein (B) in BALF as compared with changes seen after saline instillation. Within 5 min of instillation there was a rapid rise in measured kinin concentrations in BALF. This rise was significantly greater than that seen after saline instillation. The response was rapid with kinin concentrations returning toward baseline values within 15 min. Changes in total protein mirrored the changes seen with kinin; however, because of the variability in the response the difference was not statistically significant with respect to the saline.
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Effect of PPE on Tracheal Smooth Muscle Contraction In Vitro
PPE did not produce an increase in tracheal smooth muscle
tension in any of the four preparations. This is compared with
the response seen with carbachol (105 M), which increased
tracheal smooth muscle tension to 21 ± 4 g.
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The results of this study are the first data indicating that inhaled HA, in a dose-dependent and molecular weight-dependent fashion, protects against inflammatory mediator-induced bronchoconstriction in vivo. This protection is associated with inhibition of the PPE-induced increase in BALF TK activity, which is the enzyme responsible for the production of the spasmogens lysyl-bradykinin and bradykinin. Our current finding that airway exposure to PPE increases lung kinin concentrations is consistent with the physiologic data and is supportive of our previous findings that PPE-induced bronchoconstriction can be blocked with a bradykinin antagonist (20).
The rationale for our work stemmed from previous studies conducted in this laboratory that showed that inhaled PPE caused bronchoconstriction, which could be blocked by the bradykinin B2 receptor antagonist NPC-567. Because we also found that the increase in BALF TK activity was associated with this constrictor response, we concluded that the bronchial response was likely a result of the local release of kinins (20). In this previous study, however, we did not actually measure lung kinin concentrations after PPE challenge because we had previously established the relationship between increased TK activity, increased BALF kinin levels, and protection of an associated bronchoconstrictor response with NPC-567 (16). It is important to note that we had also shown that NPC-567 blocks bradykinin-induced bronchoconstriction in sheep (34). Our present findings that PPE can increase lung kinin concentrations and TK activity are consistent with and support our previous conclusions. Furthermore, these findings support our hypothesis concerning the mechanism of PPE-induced bronchoconstriction.
The addition of PPE to sheep tracheal smooth muscle preparations in amounts in excess of what was given by inhalation resulted in no contractile response in vitro. Our findings in sheep airways are consistent with previous reports demonstrating the inability of elastase to contract pig (35) and rabbit airway smooth muscle preparations (36). Thus, the constrictor effect elicited by PPE appears to be indirect.
We used instillation challenge rather than aerosol challenge to better control our ability to measure the time course of kinin formation in the lung. As seen in Figure 5A the maximal response seen was within 5 min after instillation. This time course corresponds to the maximal increase in RL seen with aerosol challenge. It is important to note that the time course of the increase in lung kinin concentrations and not the time course of the increase in TK activity, is the important correlate to the broncochonstrictor response because unless TK has available substrate, (i.e., high and low molecular weight kininogen) there can be no kinin formation. Thus, one can have situations in which TK is elevated, but RL is normal. For example, 24 h after antigen challenge, sheep show increased BALF TK activity, but RL has returned to prechallenge values. If, however, animals with increased TK activity but normal RL, inhale high molecular weight kininogen, a bronchoconstriction ensues, which as expected, can be blocked by the bradykinin B2 receptor antagonist NPC-567 (18). The observation that total proteins are also increased after PPE challenge is consistent with kininogen availability, kinin formation, and the bronchial response observed in the present study.
As mentioned, our observations in vitro, which showed that HA binds to bronchial TK and reduces its activity (30), coupled with our extensive physiologic data, suggested to us that, in vivo, inhaled HA should inhibit PPE-induced bronchoconstriction. Our data show that the protective effect shown by inhaled HA was both dose-dependent and molecular weight- dependent. This finding is reasonable given the molecular structure of HA. Because HA is a long linear polymer formed by repeat units, it is conceivable that a heavier and therefore longer HA molecule carries more binding sites for TK. A similar argument would apply to increased concentrations of the same molecular weight HA. As illustrated in Figure 4, the effect of two different concentrations of HMW-HA (one that was effective in blocking the PPE-induced bronchoconstriction: 0.05%, and one that was ineffective: 0.005%) on BALF TK activity after PPE challenge supports this concept.
Whereas our data may be the first to show functional protection of inhaled HA against PPE-induced bronchoconstriction, other investigators have used inhaled HA to protect against elastase-induced structural changes. Cantor and coworkers (37) showed that HA prevents elastase-induced emphysema in hamsters by forming a protective coating over the elastic fibers in the lung, thereby limiting elastase-induced degradation. The mechanism of this protection is unknown, but it is not caused by a direct interaction between HA and elastase, because HA does not interfere with elastase enzymatic activity in vitro. Some reports claim that LMW-HA causes the induction of inflammatory factors through a CD44-mediated mechanism (38). In our study, however, we did not observe any inflammatory response in the animals that received LMW-HA. Our observation is consistent with data from Lackie and coworkers (39), who showed that CD44-mediated actions in the airways are associated with repair rather than with inflammatory processes.
Previous studies from this laboratory have indicated that the regulation of TK in the airways may be important in airway pathophysiology (18). However, the sources for increased TK activity are not completely understood. TK is known to be contained in submucosal glands and, in vitro, neutrophil elastase causes the release of TK from primary cultures of ovine tracheal gland cells (19). This elastase-induced submucosal gland release of TK may be an important stimulus for kinin-induced airway inflammation. Such a mechanism may be important in asthma because free elastase activity is increased in BALF of allergic sheep (21) and human sputum of patients during asthma exacerbations (22). Interestingly, HA is also elevated in BALF of asthmatic patients after antigen provocation (40), indicating that its turnover is altered in these subjects. Because HA is susceptible to degradation by oxygen radicals (41), it is interesting to speculate that antigen-induced leukocyte recruitment could contribute to the increased TK activity in the bronchial lumen both through elastase-induced TK release and oxygen radical- induced HA degradation.
In conclusion, our findings support the hypothesis of a functional protection of HA in the airways. Furthermore, they add new evidence that hyaluronan may play a pivotal role in regulating TK activity in vivo, shedding a new light on the biologic actions of this polysaccharide.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Mario Scuri, M.D., Department of Research, Mount Sinai Medical Center, 4300 Alton Road, Miami Beach, FL 33140. E-mail: mscuri{at}MSMC.com
(Received in original form November 27, 2000 and accepted in revised form September 20, 2001).
This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org
Acknowledgments:
Supported in part by NIH Grant 03534.
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References |
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