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*
Laboratory of Inflammation and
Laboratory of Pathology, Institute Oswaldo Cruz, Fiocruz, Brazil;
Leukocyte Biology Section, Imperial College School of Medicine, London, United Kingdom; and
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Based on the highly allergenic nature of helminthic parasites and on their particular ability to promote proallergic activities, including mastocytosis, IgE synthesis, and eosinophilia, several groups have postulated a causal link between helminthic infection and the development of allergic diseases (for review, see Ref. 6). However, both epidemiological and laboratory studies indicate that populations parasitized with helminths are actually less responsive to allergen challenge. For instance, there is an inverse relationship between helminth infection and incidence of allergies in human populations (7). Furthermore, decreases in both serum IgE and circulating eosinophil levels by treatment with antihelminthic drugs appeared clearly associated with enhancement of allergic reactivity (7, 8). According to these authors, the lower incidence of allergic reactions in humans infected with parasites would be accounted for by an increased polyclonal IgE production, causing receptor saturation and therefore suppression of specific IgE sensitization (for review, see Ref. 9).
Likewise, in experimental models of human allergic reactivity, helminth-infected rats are less reactive to cutaneous anaphylactic reactions than uninfected rats (10, 11, 12). Several other studies have demonstrated that tissue eosinophilia, caused by Mesocestoide corti or Toxocara canis, is closely related to down-regulation of inflammatory responses in different in vivo and ex vivo models (13, 14, 15). In line with these findings, previous studies by our group have demonstrated that rats undergoing localized eosinophilia induced by exogenous chemoattractants, or even expressing spontaneous eosinophilia, reacted to allergen-induced challenge with an attenuated pleural edema. This phenomenon, which was clearly reversed by either pharmacological or immunological blockade of the eosinophilia, also seemed to be dependent on PGs (16, 17, 18).
To define in more detail the interactions between parasitic infections and allergic inflammation, we have in this study investigated the effects of infection with A. costaricensis on allergen-evoked pleurisy in rats. Since, under our particular conditions, helminth infection reduced the duration of allergic edema, we further investigated the mechanisms involved in this phenomenon, assessing the contributions of the isoforms of cyclooxygenase (COX),3 PGE2, and lipoxin A4 (LXA4) to the regulation of this response to immunological challenge.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Wistar rats of either sex and weighing 150–200 g, purchased from the Oswaldo Cruz Foundation Breeding Unit (Rio de Janeiro, Brazil), were used.
Allergic pleurisy in passively sensitized rats
Rats were passively sensitized by means of an intrapleural (i.pl.) injection of murine IgE mAb to DNP (anti-DNP; 1 µg/cavity). Twenty-four hours later, the allergen, dinitrophenylated BSA (DNP-BSA; 1 µg/cavity), was injected i.pl. into sensitized and sham-sensitized animals (sensitization in which sterile isotonic saline replaced murine IgE anti-DNP). All i.pl. injections were performed during light ether anesthesia in a final volume of 100 µl using a 27.5-gauge needle adjusted to be 3 mm in length, and all solutions were prepared immediately before use. At different times after pleural stimulation, the animals were killed with terminal ether anesthesia and the thoracic cavity was rinsed with 3 ml of saline-containing heparin (10 IU/ml).
Infection with parasite
The nematode Angiostrongylus costaricensis has been maintained in the Department of Pathology of Institute Oswaldo Cruz (Fiocruz, Rio de Janeiro, Brazil) through two hosts, mice and Sarasinula sp slugs. The infective larvae (third-stage larvae, L3) of this parasite, harvested from mollusc mucus, were counted under a dissecting microscope and diluted in saline. Unsensitized rats were infected by oral administration of 300 infective larvae (L3) of A. costaricensis. Twenty-five days later, infected rats were passively sensitized with an IgE anti-DNP-BSA and subsequently challenged as described above.
Pretreatment with IL-5
IL-5 i.v. (100 IU/kg) was diluted in sterile saline (final volume of 200 µl) and injected i.v. in naive rats, anesthetized with ether. One hour later, again anesthetized, rats were passively sensitized and subsequently challenged, as described above.
Pretreatment with COX inhibitors or eicosanoids
The COX inhibitors, indomethacin (2 mg/kg), aspirin (200 mg/kg), NS-398 (5 mg/kg), SC-236 (0.5 mg/kg), and meloxicam (1 mg/kg), were given i.p. 1 h before allergic challenge. Misoprostol (200 µg/kg) was orally administered 1 h before allergic challenge. In control groups, the inhibitors were replaced with their vehicles. The LXA4 analogues, 15-methyl-LXA4 and 15-epi-16-p-fluorophenoxy-LXA4, were given locally 5 min before allergic challenge. All of the solutions were prepared immediately before use and, except indomethacin, NS-398, SC-236, and the LXA4 analogues, which were dissolved in saline. Indomethacin was dissolved in 0.1 N NaOH, buffered with Tris, and neutralized with 0.1 N HCl. NS-398 and SC-236 were dissolved in DMSO and further diluted in saline. The LXA4 analogues were dissolved in ethanol and further diluted in saline.
Measurement of the kinetics of vascular permeability increase, fluid accumulation, and total protein exuded
Microvascular permeability was assessed in several periods of time, including the first 10 min, from 10–30 min, from 30–60 min, from 60–120 min, and from 120–240 min postallergen challenge. The analysis was done by giving the Evans blue dye i.v. either 5 min before challenge, at 10, 30, 60, or 120 min postchallenge, and thus represents the state of the microvasculature in each of these periods. This type of sample contrasts with that for fluid accumulation, which measured all of the fluid present at the appropriate time, i.e., net accumulation with fluid exudation balanced against reabsorption, for the whole of the sampling period, ranging from 10–240 min postchallenge. Pleural washings were collected and its volume measured with a graduated syringe. Analysis of the plasma protein leakage was performed at different times after injection of allergen. The fluid collected from the pleural cavity was centrifuged (1300 x g) for 10 min, and the protein content of the supernatant was measured by the biuret technique (19). Evans blue dye exuded was quantified by means of spectrophotometric analysis at 650 nm.
Cell analysis
Total leukocytes from peripheral blood (from the tail vein) and pleural cavity were counted in Neubauer chambers by means of an optical microscope after dilution with Türk’s solution (2% acetic acid). Differential analysis of cells from blood and pleural fluid was made in blood smears and cytospin preparations, respectively, stained with May-Grünwald-Giemsa dye under an oil immersion objective.
PGE2, LTC4, and LXA4 measurements
Pleural exudates were collected with 1 ml of saline containing heparin (10 IU/ml) and indomethacin (50 µg/ml) to prevent further production of PGE2. The pleural fluid samples were centrifuged at 1300 x g for 10 min at 0°C, and the supernatants were mixed with methanol (200 µl). The eicosanoids in the pleural supernatant were extracted with SEP-PAK C18 cartridges (Waters Associates, Milford, CT), as previously reported. PGE2, LTC4, and LXA4 levels were measured with ELISA kits according to the manufacturer’s instructions (Neogen, Lexington, KY). LXA4 was further identified by liquid chromatography/mass spectrometry/mass spectrometry analysis using the LXA4 molecular ion m/z 351 and a retention time of synthetic LXA4 standard, as in Clish et al. (20).
Measurement of corticosterone in serum
Blood samples were taken from the abdominal aorta immediately after death. Serum corticosterone levels were determined using an RIA test kit, according to the instructions of manufacturer (ICN Pharmaceuticals, Costa Mesa, CA).
Materials
Murine anti-dinitrophenylated (DNP) mAb was kindly provided by Dr. A. Provoust-Danon (Unité d’Immuno-Allergie, Institut Pasteur, Paris, France). Indomethacin, Evans blue dye, DNP-BSA, and IL-5 were from Sigma (St. Louis, MO); aspirin was from Synthelabo France Laboratories (Paris, France); meloxicam (Movatec ampoules) was from Boehringer Ingelheim (Buenos Aires, Argentina); and NS-398 was from BIOMOL Research Laboratories (Philadelphia, PA). Misoprostol (Cytotec tablets) was a gift from BIOLAB (São Paulo, Brazil), and SC239 was kindly donated by Searle (Skokie, IL). The LXA4 analogues used in these experiments were prepared by Dr. Nicos Petasis’ laboratory (Department of Chemistry, University of Southern California) as part of a sponsored research program with the C.N.S. laboratory, Brigham and Women’s Hospital/Harvard Medical School.
Statistical analysis
Data are reported as means (±SEM) and statistically analyzed by means of ANOVA, followed by the Newman-Keuls-Student’s test. Differences were considered to be statistically significant when p < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The kinetics of the development of the allergic edema are
illustrated in Fig. 1
, as changes in
microvascular permeability measured by Evans blue dye in the pleural
fluid (Fig. 1a) and as total volume of fluid accumulated in
the pleural cavity (Fig. 1b). These two variables were
measured at the same times after Ag challenge, but represent different
types of sampling, as indicated in Materials and Methods. As
shown in Fig. 1a, the increase in microvascular permeability
induced by allergen challenge was restricted to the first 10 min
postchallenge, with all subsequent assays revealing normal
microvascular permeability. In contrast, the volume of pleural fluid
essentially plateaued from 10 to 240 min (Fig. 1b), falling
to background value 24 h postchallenge (data not shown). These
kinetics suggest that the magnitude of the edema was determined by the
early increase in microvascular permeability, and that the duration was
determined by reabsorptive processes, with negligible continuing
exudation over the 4-h period.
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In noninfected rats, allergen challenge induced no increase in the
eosinophil numbers in the pleural cavity at 30 min or at 4 h after
challenge (Fig. 2) and no changes in
peripheral blood leukocyte numbers. By contrast, 25 days after A.
costaricensis infection, there was a marked and selective increase
in eosinophil numbers in peripheral blood, from 0.2 ± 0.1 to
1.1 ± 0.2 x 103 eosinophils/µl
(mean ± SEM, n = 8, p < 0.01) in
normal and infected rats, respectively.
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, c and e. In contrast, analysis
performed 4 h after allergen showed a striking increase in pleural
eosinophil infiltration (Fig. 2d), together with a drastic
decrease in the protein amount of pleural exudate in infected rats
(Fig. 2f). The development of pleural eosinophilia was
accompanied by a small reduction in the underlying blood eosinophilia
(Fig. 2, a and b). Pretreatment with IL-5
Intravenous stimulation with IL-5 (100 IU/kg) significantly
increased circulating eosinophil numbers within 1 h, from 0.1
± 0.1 to 0.5 ± 0.1 x 103 eosinophils
per µl (mean ± SEM, n = 8, p <
0.01), respectively, in normal and IL-5-treated rats, under conditions
in which pleural protein content and leukocyte counts were not altered.
As shown in Fig. 3, c and
e, IL-5 pretreatment did not affect the allergic pleural
exudation or eosinophil accumulation over 30 min, but reduced the
allergic edema at 4 h after challenge and induced a selective
pleural eosinophilia (Fig. 3, d and f).
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Total serum corticosterone was determined by RIA from samples collected 4 h after allergen challenge of A. costaricensis-infected rats. Corticosterone levels obtained in sham-sensitized animals (108 ± 47 ng/ml, n = 6, mean ± SEM) were not modified by either allergic challenge or helminth infection, showing values of 81 ± 28 and 106 ± 25 ng/ml, respectively. In addition, the combination of both treatments (allergic challenge and infection) also failed to evoke systemic alterations in corticosterone levels, with values of 101 ± 27 ng/ml.
Fig. 4 summarizes the levels of the
eicosanoids, PGE2, LXA4,
and LTC4, in pleural fluids at 4 h following
allergen challenge. Infection with A. costaricensis led to a
5-fold increase of PGE2 in pleural fluid over the
values in noninfected animals (Fig. 4a). As illustrated in
Fig. 4b, the LXA4 content of pleural
fluid was raised by infection alone and elevated further after allergen
challenge. The generation of endogenous LXA4 was
confirmed by liquid chromatography/mass spectrometry/mass spectrometry
analysis (20). No significant changes in
LTC4 content of pleural fluid were noted after
allergic challenge or after infection with the helminth (Fig. 4c).
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Pretreatment with either of the nonselective COX inhibitors,
indomethacin (2 mg/kg, i.p.) or aspirin (200 mg/kg, i.p.), 1 h
before challenge failed to modify allergen-induced protein exudation in
IgE passively sensitized rats (17). As summarized in Table I, these inhibitors also did not affect
allergen-evoked pleural eosinophil accumulation observed at 4 h in
rats with A. costaricensis infection, but they did reverse
the reduction of the edema. Likewise, in rats with an IL-5-dependent
eosinophilia, indomethacin (2 mg/kg, i.p.) also restored
allergen-induced edema at 4 h without modifying the local
eosinophilia (Table II).
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B), without affecting the
concurrent pleural eosinophilia (Fig. 5a). In
IL-5-pretreated rats, the highly selective COX-2 inhibitor, SC-236,
also restored the allergic edema without modifying pleural eosinophilia
(Table II).
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In the first set of experiments, the pleural exudation in response
to allergen challenge was analyzed at three points after allergen
challenge, 15 min, 1 h, and 4 h. As shown in Table III, the edema was maintained from 15 min
to 4 h, and for the first two time points, this response was not
affected by oral pretreatment with the synthetic PG analogue,
misoprostol (200 µg/kg). However, misoprostol did inhibit the edema
at 4 h postchallenge, to about 55% of the previous value.
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, c and d) and
15-epi-16-p-fluorophenoxy-LXA4 (Fig. 6, a and b). These LXA4
stable analogues that resist rapid metabolic inactivation of
LXA4 did not affect exudation measured at 15 min
(Fig. 6, a and c) after allergen challenge, but
reduced that at 4 h, in a dose-dependent manner (Fig. 6, b and d).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In both models, we observed a curtailment of the duration of the allergic edema, concomitantly with pleural eosinophil accumulation. In both models, there was clear evidence for the involvement of COX-2 in the accelerated resolution of allergen-induced edema. We were also able to mimic the ability of infection or IL-5 pretreatment to shorten the duration of the allergic edema response by systemic administration of misoprostol, a synthetic PGE analogue, or local, i.pl. treatment with LXA4 analogues.
Despite abundant evidence of the decreased incidence of allergic
disorders in patients or experimental animals with existing helminth
parasitic infection, the mechanisms underlying this mutual exclusion
have been poorly investigated. Nevertheless, several attempts have been
made to define the mechanisms responsible for the inverse relationship
between parasitic infection and allergies. The presently prevailing
hypothesis proposes the elevated synthesis of nonspecific polyclonal
IgE in helminthic infection as being responsible for the suppression of
allergic inflammation, because such an increased synthesis could lead
to a saturation of Fc
receptors (9). Another
explanation considers the suppressive mechanism to be inhibition of
allergen-specific IgE synthesis by the polyclonal response against the
parasites (7).
Other studies have suggested that allergic activation of mast cells is inhibited by a variety of factors, including the parasitosis-related soluble Ag/IgE complex (21), or rat C3a fragments (22) or human IgG4 (23). However, all of these possible mechanisms operate by inhibiting the capacity of mast cells to react to stimulation with allergen, a process essential for the initiation of the allergic response. As such, these explanations are unlikely to apply to our experimental findings, as the failure in allergic response we observed in this study was always a failure of duration and not of initiation, of the allergic response. Indeed, initiation of allergic responses is most likely to be controlled by factors such as the production or binding of anaphylactic Abs, or receptor activation. In our experiments, both noninfected and helminth-infected rats were sensitized with the same amount of IgE anti-DNP mAb and mounted comparable allergic pleural exudatory responses, showing no differences in the initial development of the edema.
A further mechanism involved in the lower occurrence of allergic reaction in parasitized individuals, which might also account for our observation of shorter duration of edema in A. costaricensis-infected rats, is overproduction of anti-inflammatory corticosteroid hormones (24, 25) induced by the helminth infection. However, in our model, we did not find any alteration in serum corticosterone level in A. costaricensis-infected rats even after allergic challenge, indicating that yet another mechanism should underlie the curtailment of allergic edema noted in infected animals in our model.
It is particularly relevant to note in this work that helminth parasitic infection is perhaps the most powerful stimulus for blood and tissue eosinophilia. Consistent with this, we found a marked increase in peripheral blood eosinophil numbers following A. costaricensis infection in rats. This eosinophilia was long lasting and it did not affect the onset of the pleural edema following Ag challenge. We have also previously shown that pleural eosinophilia, induced by local administration of eosinophil attractants such as platelet-activating factor, ECF-A, bacterial LPS, and pleural wash from LPS-treated rats (16, 17, 18), also promotes an attenuation of allergen-induced pleural edema within 4 h. Selective inhibition of eosinophil influx by either immunological or pharmacological means diminished the curtailment of allergic edema, reinforcing the relationship between eosinophilia and down-regulation of allergic edema (16, 18).
A constant concomitant of the shorter lasting allergic edema in helminth-infected rats was local, i.e., pleural, eosinophilia. It was also remarkable that the allergic edema was modified only at the later stages of the overall response when eosinophil accumulation in the pleural cavity had occurred and not in the early stages, at about 30 min after Ag challenge, when eosinophil numbers in the pleural cavity were still low. Because eosinophilic responses in helminthic infections are known to be dependent on IL-5 (2), we also assessed another model in which the direct administration of IL-5 was used to induce eosinophilia in uninfected animals. In agreement with other studies (26, 27, 28), injection of IL-5 induced circulating eosinophilia that, like that observed in A. costaricensis-infected rats, gave rise to a pleural eosinophil infiltration within 4 h and an accelerated resolution of allergic edema without affecting its onset. These observations and our earlier work suggested that some component of the process of eosinophilia exerted an anti-inflammatory effect.
One possible mediator of the phenomenon we have described in this work, i.e., the shortening of allergic edema related to a local eosinophilia, is PGE2. Although this PG can act as a proinflammatory agent, inducing vasodilatation and synergizing with other proinflammatory mediators to promote protein exudation and hyperalgesia, it has also been shown to down-regulate inflammatory responses, including allergic reactions, impairing activation of pivotal leukocytes (29). PGE2 is one of the eicosanoids produced by eosinophils (30, 31), and Buijs et al. (15) had noted that parasitic infection increased the biosynthesis of PGE2 concurrent with eosinophilia. Furthermore, allergic stimulation raised PGE2 production in pleural cavities that were experiencing a concurrent selective eosinophilia induced by eosinophil chemoattractants (17, 18).
Our present experiments have directly confirmed an anti-inflammatory role for PGE2 and further suggested that LXA4 in this model may also contribute to the overall impact. Thus, levels of PGE2 were increased at the late stages, but only in animals both infected and challenged. Administration of the synthetic PG misoprostol, which acts on the same receptors as PGE2, caused a shortening of duration of allergic edema in uninfected rats without affecting the onset of edema. Finally, inhibition of PGE2 biosynthesis with a range of COX inhibitors reversed the curtailment of the edema in infected or IL-5-treated rats, again without affecting onset. All of these findings would support an important contribution from PGE2 in mediating the accelerated resolution of edema. Biosynthesis of PGE2 is catalyzed by COX, which is now known to exist as two isoforms, both expressed by eosinophils. COX-1 is a constitutively expressed enzyme, whereas COX-2 is strongly induced by proinflammatory agents such as cytokines and endotoxin (for review, see Ref. 32). The inhibitors used in this study included nonselective inhibitors of both isoforms (indomethacin, aspirin) and more selective COX-2 inhibitors (meloxicam, NS 398, and SC 236) (32, 33). None of them affected the onset of edema or the subsequent eosinophilia, leading to the conclusion that, in these conditions, neither isoform was crucial to the onset of the edema. These findings would contrast with the clear suppression of other forms of inflammatory edema (e.g., paw edema, air pouch exudation, carrageenin pleurisy) by COX inhibitors, and this discrepancy may reflect the allergic stimuli used in this study. However, at the later stages of the experiment (4 h), the efficacy of the selective COX-2 inhibitors SC 236 and NS 398 would imply that this isoform was crucially involved in the formation of the PGE2 that induced the early resolution of the edema. This suggestion of a late, anti-inflammatory effect of COX-2, instead of the more widely recognized early, proinflammatory action, has recently been supported by results from another rat pleurisy model, induced by carrageenin (34). In these studies, although the selective COX-2 inhibitor NS 398 and indomethacin both inhibited inflammation at 2 h, later administration at 48 h caused an exacerbation of the pleurisy, comparable with our observations. Our experiments also showed no effect of COX inhibition on the development of pleural eosinophilia either in infected rats or after IL-5 pretreatment, a finding in agreement with others showing that eosinophil accumulation is not affected by COX inhibitors (35, 36).
A degree of selectivity of stimulation of eicosanoid production and hence of action at the later stages of the allergic edema (about 4 h) is inferred from the lack of increase in LTC4, whereas LXA4 was increased either by infection alone or, more strikingly, after allergen challenge in infected animals. Here too, synthetic analogues of the endogenous LXA4 were able to reduce edema at 4 h, but not at 15 min, after challenge. Eosinophils are known to secrete LXA4 (37), and this lipoxin exhibits anti-inflammatory actions in both in vitro and in animal assays, acting as an endogenous stop signal to inflammatory reactions (38).
In conclusion, our results suggest that local increases in COX-2-derived PGE2, and in LXA4, occurring some hours after the initiating allergen challenge, accelerate the resolution of pleural edema evoked by allergen in A. costaricensis-infected or IL-5-treated rats. Although the source of these eicosanoids is not definitely known, it is most likely that they are derived from the eosinophils concurrently accumulated in the pleural cavity. The exact effects of these eicosanoids by which the accelerated resolution of allergic edema is achieved (for instance, increased blood or lymphatic flow) remain to be determined. However, our findings do provide a new, localized mechanism by which the eosinophilia induced by parasitic infections can decrease inflammatory reactions to Ag challenge, and one that does not affect the initiation of the response, but its duration. Whether or not eosinophilia can modulate other signs of inflammation such as pain, and what is the real impact of a shorter duration of edema in the totality of the inflammatory response remain to be established. Our results would also support the general concept that COX-2 can mediate some tissue repair processes, as in wound healing (see, for instance, Refs. 39 and 40) and resolution of edema (34 ; present results). The inhibition of such processes may emerge as unwanted effects of selective COX-2 inhibitors in inflammatory disease.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Marco A. Martins, Laboratory of Inflammation, Department of Physiology and Pharmacodynamics. Oswaldo Cruz Institute, Fiocruz. Av. Brasil, 4365, Manguinhos, Rio de Janeiro, RJ, Brazil, 21045-900. E-mail address:
3 Abbreviations used in this paper: COX, cyclooxygenase; i.pl., intrapleural; LTC4, 5(S)-hydroxy-6(R)-S-glutathionyl-7,9-trans-11,14-cis-eicosatetraenoic acid; LXA4, lipoxin A4.
Received for publication August 23, 1999. Accepted for publication November 1, 1999.
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