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J Appl Physiol 84: 222-228, 1998;
8750-7587/98 $5.00
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Inhibition of allergic airway responses by inhaled low-molecular-weight heparins: molecular-weight dependence

José Martinez-Salas, Richard Mendelssohn, William M. Abraham, Bernard Hsiao, and Tahir Ahmed

Division of Pulmonary Diseases, University of Miami School of Medicine, Mount Sinai Medical Center, Miami Beach, Florida 33140

    ABSTRACT
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

Martinez-Salas, José, Richard Mendelssohn, William M. Abraham, Bernard Hsiao, and Tahir Ahmed. Inhibition of allergic airway responses by inhaled low-molecular-weight heparins: molecular-weight dependence. J. Appl. Physiol. 84(1): 222-228, 1998.---Inhaled heparin prevents antigen-induced bronchoconstriction and inhibits anti-immunoglobulin E-mediated mast cell degranulation. We hypothesized that the antiallergic action of heparin may be molecular weight dependent. Therefore, we studied the effects of three different low-molecular-weight fractions of heparin [medium-, low-, and ultralow-molecular-weight heparin (MMWH, LMWH, ULMWH, respectively)] on the antigen-induced acute bronchoconstrictor response (ABR) and airway hyperresponsiveness (AHR) in allergic sheep. Specific lung resistance was measured in 22 sheep before and after airway challenge with Ascaris suum antigen, without and after pretreatment with inhaled fractionated heparins at doses of 0.31-5.0 mg/kg. Airway responsiveness was estimated before and 2 h postantigen as the cumulative provocating dose of carbachol in breath units that increased specific lung resistance by 400%. All fractionated heparins caused a dose-dependent inhibition of ABR and AHR. ULMWH was the most effective fraction, with the inhibitory dose causing 50% protection (ID50) against ABR of 0.5 mg/kg, whereas ID50 values of LMWH and MMWH were 1.25 and 1.8 mg/kg, respectively. ULMWH was also the most effective fraction in attenuating AHR; the ID50 values for ULMWH, LMWH, and MMWH were 0.5, 2.5, and 4.7 mg/kg, respectively. These data suggest that 1) fractionated low-molecular-weight heparins attenuate antigen-induced ABR and AHR; 2) there is an inverse relationship between the antiallergic activity of heparin fractions and molecular weight; and 3) ULMWH is the most effective fraction preventing allergic bronchoconstriction and airway hyperresponsiveness.

airway hyperresponsiveness; mast cells

    INTRODUCTION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

HEPARIN IS A HIGHLY SULFATED linear polysaccharide comprising repeating 1 right-arrow 4 linked uronic acid and glucosamine residues (19, 23). The complexity of heparin structure and function results from its polydispersity and its heterogenous molecular organization (22, 23). The basic polymeric structure of heparin is an alternating repeat sequence of the disaccharide units that can be variably sulfated (22, 23). The sugar sequence and degree of sulfation confer on the heparin molecule its unique chemical properties as a pharmacological mediator (10, 19, 22, 23). Because of its high charge density, the presence of a specific sequence (for antithrombin III) on a subpopulation of its chains, and a relatively nonspecific sequence on the majority of chains, heparin is able to interact with clusters of basic amino acids on numerous proteins, allowing heparin to bind many enzymes and modulate various biological processes (19, 22, 23).

The structural variability is often the basis of a wide variety of domain structures with a number of biological activities ascribed to heparin. Thus, in addition to its most widely recognized anticoagulant activity, the heparin molecule has multiple "non-anticoagulant" properties that include modulation of various proteases (26, 27), regulation of cellular proliferation (9, 32), and anti-inflammatory and immunoregulatory properties (12, 31), including the modulation of T lymphocytes (21), inhibition of neutrophil chemotaxis (25), and eosinophil influx (28).

Although the precise role of endogenous mast cell heparin is not known, it has recently been demonstrated that commercial heparin possesses significant antiallergic activity (1, 24). Thus inhaled heparin was shown to attenuate antigen-induced bronchoconstriction in allergic sheep (1) as well as to prevent the bronchoconstrictor response to exercise (4, 15) and antigen in asthmatic subjects (8, 11). Because many biological actions of heparin are molecular weight dependent (20), we have hypothesized that low-molecular-weight heparin fractions may have greater potency and thus may inhibit airway anaphylaxis at much smaller doses. Therefore, we studied the effect of three different low-molecular-weight heparin fractions [medium-molecular-weight heparin (MMWH) KABI 2165; low-molecular-weight heparin (LMWH) CY216; and ultralow-molecular-weight heparin (ULMWH) CY222] on antigen-induced acute bronchoconstrictor response (ABR) and airway hyperresponsiveness (AHR).

    MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

Animal Preparation

Twenty-two adult sheep (mean weight 29 kg, range 26-34 kg) were included in the study. All sheep were allergic to Ascaris suum antigen and had previously been shown to develop "acute bronchoconstriction" only after inhalation challenge with the antigen. The study was approved by the Mount Sinai Medical Center's Animal Research Committee.

Measurement of Airway Mechanics

Mean pulmonary airflow resistance was measured in conscious intubated sheep by using the esophageal balloon technique, and thoracic gas volume was measured by body plethysmography by using the techniques previously described (1, 3). Data were expressed as specific lung resistance (sRL), defined as lung resistance × thoracic gas volume.

Aerosol Delivery System

Aerosols were generated by using a Raindrop disposable nebulizer (Puritan Bennett, Lenexa, KS), which produces an aerosol with a mass median aerodynamic diameter of 3.2 µm (geometric SD 1.9). The output from the nebulizer was directed into a plastic T piece, which was interconnected between the Harvard animal respirator and the endotracheal tube. To control the aerosol delivery, a dosimeter system was used, consisting of a solenoid valve and a source of compressed air (20 pounds/in.2), which was activated for 1 s at the beginning of the inspiratory cycle of the Harvard respirator system. All aerosols were delivered at a tidal volume of 500 ml and a rate of 20 breaths/min.

Agents

Ascaris suum extract (Greer Diagnostics, Lenoir, NC) was diluted with buffered saline to a final concentration of 82,000 protein nitrogen units/ml and delivered as an aerosol over 20 min (400 breaths). The dose of antigen delivered was kept constant for all animals, in all antigen experiments. Carbachol (Sigma Chemical, St. Louis, MO) was dissolved in phosphate-buffered saline for nebulization. MMWH (KABI-2165; mol wt 5,030) was obtained from Pharmacia (Stockholm, Sweden), whereas LMWH (CY216; mol wt 4,270) and ULMWH (CY222; mol wt 2,355) were obtained from Sanofi Pharma (Gentilly, France). The molecular-weight distribution, anti-factor Xa, and APTT activities of heparin fractions are shown in Table 1.

                              
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  		Table 1.   Molecular weight and characteristics of heparin fractions

Experimental Protocol

For every protocol, each animal was studied on 3 different experimental days. On experiment day 1, baseline bronchial reactivity to carbachol was determined, whereas on experiment days 2 and 3 the bronchial reactivity to carbachol was redetermined (at least 2 wk apart) 2 h after the antigen challenge, without or after pretreatment with different doses of fractionated heparins. Group I (n = 7) was pretreated with aerosolized MMWH KABI-2165 (1.25-5 mg/kg); group II (n = 8) was pretreated with aerosolized LMWH CY216 (0.31-5 mg/kg); and group III (n = 7) was pretreated with ULMWH CY222 (0.31-5 mg/kg).

Bronchial reactivity to carbachol. To assess baseline airway responsiveness, cumulative dose-response curves to inhaled carbachol were performed on experiment day 1 by measuring sRL before and immediately after inhalation of buffered saline and after each administration of 10 breaths of increasing concentrations of carbachol [0.25, 0.5, 1.0, 2.0, 3.0, and 4.0% (wt/vol) solution]. The bronchoprovocation was discontinued when sRL increased to 400% above the baseline. The cumulative provocating dose of carbachol (in breath units) that increased sRL to 400% above baseline (PD4) was calculated. One breath unit was defined as 1 breath of a 1% carbachol solution. Baseline dose-response curves to carbachol were performed in all sheep at least 2 wk after their last exposure to antigen.

Effects of low-molecular-weight heparins. The effects of each dose of three different low-molecular-weight heparins were studied on various experiment days. There was at least a 2-wk interval between the treatments. For the control antigen experiments, after baseline measurements of sRL, the sheep were challenged with aerosolized Ascaris suum antigen, and measurements of sRL were repeated within 5 min postchallenge. Two hours postchallenge, when sRL had returned to baseline, a carbachol dose-response curve was performed to determine the postantigen value of PD4 as an index of AHR.

To evaluate the effect of MMWH (n = 7) on antigen-induced ABR and AHR, the above protocol was repeated after the sheep were pretreated with various doses of aerosolized KABI-2165 (1.25, 2.5, and 5 mg/kg). Similar protocols were performed to study the effects of LMWH (CY216, n = 8) and ULMWH (CY222, n = 7). The doses of CY216 and CY222 were 0.31, 0.62, 1.25, 2.5, and 5 mg/kg. The fractionated heparins were dissolved in 3 ml of bacteriostatic injection water and administered as an aerosol 30 min before the antigen challenge.

Statistical Analysis

The data are reported as means ± SE and are analyzed by repeated-measures analysis of variance and Newman-Keuls pairwise comparison. Baseline values of PD4 were compared with postantigen PD4 (without or with drug pretreatment) by Friedman's two-way analysis of variance followed by nonparametric multiple comparison. Significance was accepted if P < 0.05 by using a two-tailed test. The power analysis showed that with n = 6 these tests give 80% power to detect sRL changes of ±1.1 cmH2O/s. Data were also expressed as percent protection of ABR and AHR
%Protection  of  ABR  =  <FR><NU>&Dgr;sR<SC>l</SC>% (control)  −  &Dgr;sR<SC>l</SC>% (drug)</NU><DE>&Dgr;sR<SC>l</SC>% (control)</DE></FR>  ×  100
%Protection  of  AHR  =  <FR><NU>PD<SUB>4</SUB> (drug)  −  PD<SUB>4</SUB> (antigen)</NU><DE>PD<SUB>4</SUB> (baseline)  −  PD<SUB>4</SUB> (antigen)</DE></FR>  ×  100

    RESULTS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

Effect of MMWH (KABI-2165, n = 7)

Pretreatment with aerosolized KABI-2165 attenuated the antigen-induced bronchoconstriction (Fig. 1, Table 2). The ABR was inhibited by 24 ± 20% [P = not significant (NS)], 84 ± 9% (P < 0.05), and 82 ± 7% (P < 0.05) by inhaled doses of 1.25, 2.5, and 5.0 mg/kg of KABI-2165, respectively. These data were in part published recently (2).


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  		Fig. 1.   Effect of pretreatment with inhaled medium-molecular-weight heparin (KABI-2165) on antigen-induced acute bronchoconstrictor response (ABR) and airway hyperresponsiveness (AHR). ABR data (A) are shown as means ± SE %change in specific lung resistance (sRL), without and after pretreatment with KABI-2165. AHR data (B) are shown as postantigen means ± SE PD4, as %baseline, without and after pretreatment with KABI-2165, where PD4 is the cumulative provocating dose of carbachol that increased sRL to 400% above baseline. * Significantly different from antigen control (P < 0.05).

                              
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  		Table 2.   Effect of pretreatment with ULMWH (CY222), LMWH (CY216), and MMWH (KABI-2165) on antigen-induced bronchoconstriction

Inhaled KABI-2165 also attenuated the antigen-induced AHR (Fig. 1, Table 3). Postantigen AHR was inhibited by 21 ± 12% (P = NS), 30 ± 11% (P = NS), and 53 ± 16% (P < 0.05) by inhaled doses of 1.25, 2.5, and 5.0 mg/kg of KABI-2165, respectively.

                              
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  		Table 3.   Effect of pretreatment with inhaled ULMW (CY222), LMWH (CY216), and MMWH (KABI-2165) on antigen-induced airway hyperresponsiveness

Effect of LMWH (CY216, n = 8)

Pretreatment with aerosolized CY216 attenuated the antigen-induced bronchoconstriction (Fig. 2, Table 2). The ABR was inhibited by -16 ± 14% (P = NS), 25 ± 15% (P = NS), 50 ± 20% (P < 0.05), 60 ± 11% (P < 0.05), and 79 ± 6% (P < 0.05) by 0.31, 0.62, 1.25, 2.5, and 5.0 mg/kg doses of CY216, respectively.


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  		Fig. 2.   Effect of pretreatment with inhaled low-molecular-weight heparin (CY216) on antigen-induced ABR and AHR. ABR data (A) are shown as means ± SE %change in sRL, without and after pretreatment with CY216. AHR data (B) are shown as postantigen means ± SE PD4, as %baseline, without and after pretreatment with CY216. * Significantly different from antigen control (P < 0.05).

Inhaled CY216 also attenuated the antigen-induced AHR (Fig. 2, Table 3). Postantigen AHR was inhibited by 32 ± 17% (P = NS), 30 ± 11% (P = NS), 48 ± 12% (P < 0.05), 49 ± 12% (P < 0.05), and 108 ± 15% (P < 0.05) by 0.31, 0.62, 1.25, 2.5, and 5.0 mg/kg doses of CY216, respectively.

Effect of ULMWH (CY222, n = 7)

Pretreatment with CY222 attenuated the antigen-induced bronchoconstriction (Fig. 3, Table 2). The ABR was inhibited by 11 ± 21% (P = NS), 75 ± 8% (P < 0.05), 78 ± 8% (P < 0.05), 79 ± 9% (P < 0.05), and 79 ± 3% (P < 0.05) by 0.31, 0.62, 1.25, 2.5, and 5.0 mg/kg doses of CY222, respectively.


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  		Fig. 3.   Effect of pretreatment with inhaled ultralow-molecular-weight heparin (CY222) on antigen-induced ABR and AHR. ABR data (A) are shown as means ± SE %change in sRL, without and after pretreatment with CY222. AHR data (B) are shown as postantigen means ± SE PD4, as %baseline, without and after pretreatment with CY222. * Significantly different from antigen control (P < 0.05).

Inhaled CY222 also attenuated the antigen-induced AHR (Fig. 3, Table 3). Postantigen AHR was inhibited by 18 ± 21% (P = NS), 68 ± 18% (P < 0.05), 107 ± 26% (P < 0.05), 131 ± 35% (P < 0.05), and 102 ± 8% (P < 0.05) by 0.31, 0.62, 1.25, 2.5, and 5.0 mg/kg doses of CY222, respectively.

Molecular-Weight Dependence

Based on the above data, the minimum effective doses and inhibitory dose causing 50% protection (ID50) of the different-molecular-weight fractions of heparin against ABR and AHR were determined. The minimum effective doses of MMWH, LMWH, and ULMWH against ABR were 2.5, 1.25, and 0.62 mg/kg, respectively, whereas the minimum effective doses against AHR were 5, 1.25, and 0.62 mg/kg, respectively (Figs. 1-3; Tables 2 and 3).

ULMWH (CY222) was the most potent agent, with ID50 of 0.5 mg/kg, against both ABR and AHR. LMWH (CY216) showed intermediate efficacy, with ID50 values of 1.25 and 2.5 mg/kg against ABR and AHR, respectively. In contrast, MMWH (KABI-2165) was the least effective agent, with ID50 values of 1.8 and 4.7 mg/kg against ABR and AHR, respectively (Fig. 4). Thus, for LMWH and MMWH, the ID50 values were lower against ABR than against AHR, whereas for ULMWH the ID50 against the two end points was the same. Overall, there was an inverse relationship between the protection of ABR and AHR and the molecular weight of fractions.


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  		Fig. 4.   Comparative protective effects of inhaled ultralow-molecular-weight heparin (CY222), low-molecular-weight heparin (CY216), and medium-molecular weight-heparin (KABI-2165) on antigen-induced ABR and AHR. Data are means ± SE %protection of antigen-induced ABR (A) and AHR (B). Thick arrows represent inhibitory dose causing 50% protection. * Significantly different from CY216 (P < 0.05). + Significantly different from KABI-2165 (P < 0.05).

    DISCUSSION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

The results of this study demonstrate that 1) fractionated low-molecular-weight heparins attenuate antigen-induced acute bronchoconstriction and AHR; 2) there is an inverse relationship between the molecular weight and the antiallergic activity of fractionated heparins; and 3) ULMWH is the most effective antiallergic fraction.

Inhaled unfractionated heparin has been shown to attenuate antigen-induced acute bronchoconstriction and postantigen AHR in allergic sheep (1, 3, 5, 6). This study further extends those observations by demonstrating that fractionated low-molecular-weight heparins, including MMWH, LMWH, and ULMWH, caused a significant inhibition of ABR and AHR. The antiallergic activity of fractionated heparins was molecular weight dependent, and an inverse relationship between the molecular weight of each fraction and its relative potency was observed. ULMWH was the most potent fraction, with ID50 against ABR of 0.5 mg/kg, whereas LMWH and MMWH fractions had ID50 of 1.25 and 1.8 mg/kg, respectively. The inhibition of postantigen AHR by each fraction was also inversely related to molecular weight and showed even greater dose dependency than the inhibition of ABR. Thus, in terms of inhibiting ABR, ULMWH was 2.5-fold and 3.5-fold more potent than LMWH and MMWH fractions, respectively, whereas it showed 5-fold and 9-fold greater potency than LMWH and MMWH in attenuating AHR.

The present study also demonstrates molecular-weight-dependent differences between the antiallergic activity of various fractionated low-molecular-weight heparins. Whereas the minimal effective doses of ULMWH inhibiting ABR and AHR were comparable, higher doses of LMWH and MMWH were required for attenuation of AHR than ABR. Thus ID50 values of ULMWH for AHR vs. ABR demonstrated a ratio of one, whereas the ID50 values of LMWH and MMWH for AHR were ~2- and 2.5-fold greater than for ABR. The reason for these differences among various low-molecular-weight heparins is not clear. In addition to the differences in molecular weight, variations in the antiallergic properties of various fractions may be linked to the saccharide chain length and/or variations in the chemical structure. Low-molecular-weight heparins are a diverse group of drugs and show considerable differences in terms of anti-Xa, anti-IIa, APTT activity, and percent glycosaminoglycan content (13, 30). In particular, ULMWH (CY222) has the highest percent glycosaminoglycan content, the lowest molecular weight, and the highest percentage of chain length <2,500. It is possible that antiallergic activity may reside in the ultralow-molecular-weight chains (i.e., <2,500) of ULMWH.

The potential differences of in vivo pharmacokinetics of various inhaled low-molecular-weight heparin fractions may partly account for quantitative differences in their antiallergic activities. Although high doses of inhaled low-molecular-weight heparin (>270 mg) show prolonged anticoagulant activity (17), the bioavailability and elimination half-life for antiallergic activity of aerosolized low-molecular-weight heparins are not known. Pharmacokinetic studies with aerosolized unfractionated heparin have demonstrated significant antiasthmatic activity lasting up to 6-12 h in sheep and 3-6 h in human subjects with asthma (5, 15). It is possible that inhaled ULMWH fractions may have better tissue penetration and bioavailability at potential sites of action, thus attenuating both ABR and AHR at very low doses. Alternatively, the potential sites and mechanisms of action of ULMWH may be different. It has been proposed that the antiallergic activity of unfractionated heparin may be mediated by inhibition of inositol 1,4,5-triphosphate-mediated mast cell mediator release (3, 6, 16, 18). Low-molecular-weight heparins have also been shown to inhibit inositol 1,4,5-triphosphate-induced Ca2+ release (29) and to attenuate anti-immunoglobulin E-induced mast cell degranulation (2). Whether the potent antiallergic activity of ULMWH observed in the present study is mediated by inhibition of mast cell-mediator release is not known at present. It is possible that inhaled unfractionated heparin, MMWH, and LMWH by acting only on mast cells may possess antiallergic activity (2, 4, 24), whereas ULMWH may also possess mast-cell-independent anti-inflammatory properties, thus inhibiting AHR at very low doses.

The antiallergic activity of inhaled unfractionated heparin observed in previous studies was related to its non-anticoagulant properties, as plasma thromboplastin time was not prolonged (1, 4, 15). This has been confirmed in a recent study demonstrating that a non-anticoagulant fraction of heparin also attenuated the antigen-induced acute bronchoconstriction in allergic sheep (2). Although in the present study anti-Xa activity was not measured, it has been shown that only very high doses of low-molecular-weight heparin (>270 mg) increase anti-Xa activity (17), thus strongly suggesting that antiallergic activity of fractionated low-molecular-weight heparins is related to non-anticoagulant properties (1, 2, 4, 15).

It has been suggested that aerosol heparin may have beneficial effects in alleviating asthma symptoms, although no definite bronchodilatory activity was observed (14). The results of this study clearly demonstrate that the antiallergic activity of heparin resides in the ultralow-molecular-weight chains. Allergic airway inflammation is closely related to AHR and plays a major role in the pathophysiology of asthma (7). Modification of allergic airway responses and AHR by ULMW heparins not only would provide further insight into the pathophysiology of asthma but may also be of clinical importance.

    ACKNOWLEDGEMENTS

We thank Teresa Della Monica for typing of the manuscript.

    FOOTNOTES

Address for reprint requests: T. Ahmed, Division of Pulmonary Diseases, Mount Sinai Medical Center, 4300 Alton Rd., Miami Beach, FL 33140.

Received 7 April 1997; accepted in final form 21 August 1997.

    REFERENCES
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

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The Journal of Applied Physiology 84(1):222-228
0161-7567/98 $5.00 Copyright © 1998 the American Physiological Society


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