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American Journal of Respiratory and Critical Care Medicine Vol 165. pp. 1531-1535, (2002)
© 2002 American Thoracic Society

Original Article

Lipoxins Are Potential Endogenous Antiinflammatory Mediators in Asthma

Caroline Bonnans, Isabelle Vachier, Claude Chavis, Philippe Godard, Jean Bousquet and Pascal Chanez

Clinique des Maladies Respiratoires, INSERM U454-IFR 3, CHU, Montpellier, France

Correspondence and requests for reprints should be addressed to Dr. Pascal Chanez, Hôpital Arnaud de Villeneuve, 371 Av du Doyen Gaston Giraud, 34295 Montpellier, Cedex 5, France. E-mail: chanez{at}montp.inserm.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Lipoxins, endogenous eicosanoids biosynthetized in vivo at inflammation sites, are potential antiinflammatory mediators. Subjects with severe asthma present chronic inflammation of the airways despite long-term treatment with oral glucocorticoids. Therefore it is of interest to investigate the potential antiinflammatory effects of lipoxin A4 (LXA4) and lipoxin B4 (LXB4) that could attenuate chronic inflammation. In a first time, we detected interleukin (IL)-8 and LXA4 in supernatants of induced sputum. IL-8 was heightened in severe asthma (p = 0.001), whereas high concentrations of lipoxin A4 were present in mild asthma (p = 0.001). We then studied the effects of LXA4 on IL-8 released in vitro. Nanomolar concentrations of LXA4 and LXB4 inhibited the IL-8 released by peripheral blood mononuclear cells from the two groups of patients with asthma: a maximal inhibition of 29.4% (p < 0.01) was observed for patients with mild asthma, and 41.5% inhibition (p < 0.001) for patients with severe asthma at 1 nM and 100 nM LXA4 concentrations, respectively. Polymerase chain reaction analysis indicated that peripheral blood mononuclear cells from patients with asthma expressed the LXA4 receptor mRNA. Moreover, pertussis toxin reversed LXA4- and LXB4-inhibited IL-8 release. These findings suggest that lipoxins have potential antiinflammatory action in asthma.

Key Words: lipoxins • asthma • inflammation • peripheral blood mononuclear cells • interleukin-8


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Lipoxins (LX) were described for the first time by Serhan and colleagues (1). Lipoxin A4 (LXA4; 5S,6R,15S-trihydroxy-7,9, 13-trans-11-cis-eicosatetraenoic acid) and lipoxin B4 (LXB4; 5S, 14R,15S-trihydroxy-6,10,12-trans-8-cis-eicosatetraenoic acid) are biologically active eicosanoids produced by lipoxygenase (LO) interactions resulting from cellular cooperations (2). On one hand, the 5-LO from neutrophils and macrophages is able to use the 15(S)-hydroxyeicosatetranoic acid released by epithelial cells as substrate to synthesize lipoxins (3). On the other hand, the platelet 12-LO (4) or macrophages 15-LO (5) are able to transform leukotriene A4, released by neutrophils, into lipoxins.

Several lines of evidence suggest that LX are mediators with putative antiinflammatory properties. LXA4 stimulates phagocytosis of apoptotic neutrophils by macrophages to resolve inflammation (6). LXA4 inhibits neutrophil transmigration across epithelial cells (7) and endothelial monolayers (8), and also inhibits tumor necrosis factor alpha–induced interleukin (IL)-1ß released by polymorphonuclear leukocytes (PMN) (9). In a recent study we demonstrated that LXA4 decreases leukotriene B4 released by human neutrophils (10). LXA4 also inhibits IL-1ß–induced IL-6 and IL-8 release in human synovial fibroblasts (11).

LXA4 exerts antiinflammatory effects via a specific high affinity G protein–coupled receptor. This seven-transmembrane domain receptor has been sequenced in human promyelocytic leukemia HL-60 differentiated cells (12) and was found in human neutrophils and monocytes (13, 14). Receptor-bound LXA4 activates in myeloid cells phospholipase A2 and phospholipase D (15). These responses are inhibited by cell pretreatment of cells with pertussis toxin (PTX).

Glucocorticoids are potent antiinflammatory agents and are widely used in the treatment of asthma (16). Although asthma in most patients is efficiently controlled with glucocorticoid treatment, some patients have severe or glucocorticoid-dependent asthma, requiring long-term systemic glucocorticoids in addition to their current treatment to control the disease (17). These patients present an ongoing inflammation of the airways, usually characterized by an increased number of neutrophils (18, 19) and activated T lymphocytes (20, 21). LXA4 has been recovered in the bronchoalveolar and nasal lavage fluids of patients with respiratory diseases (5, 22). Moreover, macrophages and neutrophils from subjects with asthma with high concentrations of 5-LO are able to synthesize LX (3, 23).

IL-8 is a chemokine that has an important role in mediating the inflammatory process in asthma. IL-8 chemoattracts and activates neutrophils (24) and eosinophils (25). IL-8 was detected in bronchial tissues of subjects with symptomatic asthma (26), and increased IL-8 concentrations have been found in induced sputum of subjects with severe asthma (20). Recently it was shown that peripheral blood mononuclear cells (PBMC) from patients with severe asthma release high concentrations of IL-8 compared with controlled and uncontrolled patients with asthma (27). Consequently, IL-8 is a putative marker of severe asthma.

The aim of the present study was to investigate the potential role of LXA4 and LXB4 as endogenous antiinflammatory mediators in asthma. To determine whether LX synthesis is involved in local inflammation, we first measured IL-8 and LXA4 contents in supernatants of induced sputum from patients with severe and mild asthma as compared with control subjects. IL-8 release was then measured in supernatants of isolated PBMC from patients with severe asthma as compared with patients with mild asthma with and without increasing doses of LXA4 and LXB4. Then, we evaluated LXA4 receptor (ALXR) expression in PBMC from the two groups of patients with asthma and control subjects at the mRNA level. We finally investigated whether the LXA4 effect on IL-8 inhibition was receptor specific.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
Subject characteristics are described in Table 1 . Twenty patients with asthma were selected according to the American Thoracic Society criteria (28). All had a reversible airway obstruction assessed by a 12% increase in FEV1 after inhalation of 200 µg of salbutamol or a positive challenge with methacholine, with at least 20% fall in FEV1 and/or a 15% increase in FEV1 after a short course of oral glucocorticoids. The clinical severity of asthma was assessed according to Guidelines for the Diagnosis and Treatment of Asthma (GINA) guidelines (29). Ten patients with mild untreated asthma receiving only ß2-agonists as required and 10 patients with severe asthma were selected as described previously (27, 30, 31). They were described as patients with severe asthma, because we failed to wean them from oral glucocorticoids in the previous 2 years, and they presented recurrent threatening episodes of acute asthma despite optimal treatment and management. They were treated on a regular basis with prednisone, inhaled fluticasone, and long acting ß2-agonists.


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  		TABLE 1. Demographic characteristics of subjects

 
Eight healthy subjects were recruited as a control group. None of them presented bronchial or respiratory disease and/or allergy. All had a negative methacholine challenge test and a negative skin prick test.

None of the subjects participating in this study was a smoker. The present study was approved by the ethics committee of our institution.

Sputum Induction and Processing
Sputum was induced according to the method of Kips and coworkers (32) and processed as described previously (33). Additional details on the method used for making the measurements is provided in the online data supplement.

IL-8 and LXA4 Assays
IL-8 (R&D Systems, Oxon, UK) and LXA4 (Cayman Chemical, Ann Arbor, MI) were measured by an enzyme-linked immunosorbent assay (ELISA) kit. The detection limits were 10 and 20 pg/ml, respectively.

Isolation and Stimulation of PBMC
PBMC from patients with asthma were isolated using Ficoll-HyPaque gradient (Amersham Pharmacia Biotech Lab, Uppsala, Sweden) as described previously (27). Isolated PBMC were resuspended at a concentration of 106 cells/ml and cultivated for 24 hours with or without LXA4 and LXB4 (Biomol, Philadelphia, PA) at increased concentrations (0.1, 1, 10, 100, and 1,000 nM).

PBMC from patients with mild (n = 3) and severe (n = 3) asthma were pretreated for 1 hour with 2 µg of PTX (Sigma-Aldrich, Steinheim, Germany) and then stimulated for 24 hours with or without 100 nM of LXA4 or LXB4 or with 100 nM of dexamethasone (Sigma-Aldrich).

Reverse Transcriptase Polymerase Chain Reaction for ALXR
Total cellular RNA was obtained by lysing cellular samples directly in TRIzol according to the manufacturer's protocol (GIBCO BRL, Glasgow, UK). Polymerase chain reaction (PCR) primers (Applied Biosystems, Foster City, CA), sense primer 5'-CAC CAG GTG CTG CTG GCA AG-3' and antisense primer 5'-AAT ATC CCT GAC CCC ATC CTC A-3' were used to amplify the published human PBMC ALXR coding region (14). In parallel, oligonucleotide primers to amplify the hypoxanthine phosphoribosyltransferase gene (HPRT) were used as the housekeeping gene (34). For additional details on the method for making these measurements, see the online data supplement.

Statistical Analysis
Data were expressed as means ± SEM. A Kruskal Wallis test was performed for comparison among three groups of subjects in addition to post hoc tests. A Mann–Whitney test was used for comparison between two groups of subjects. Student's t test was used to analyze the PTX effects. Correlations were determined using a nonparametric Spearman rank test. Differences were considered significant at the p < 0.05 level.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
Demographic characteristics of patients with mild and severe asthma and control subjects are shown in Table 1. Patients with severe asthma were older than those with mild asthma and control subjects (p = 0.01). Oral glucocorticoid requirement of patients with severe asthma was highly variable. FEV1 of patients with severe asthma was significantly lower than that of patients with mild asthma (p < 0.001) despite their ongoing glucocorticoid treatment.

IL-8 and LXA4 Concentrations in Supernatants of Induced Sputum
Measurements of IL-8 and LXA4 concentrations in supernatants of induced sputum from patients with mild (n = 7) and severe (n = 9) asthma and control subjects (n = 6) are shown in Figure 1 . Patients with severe asthma released higher IL-8 concentrations (5.1 ± 1.4 ng/ml) than those with mild asthma (1.4 ± 0.4 ng/ml, p = 0.01) and control subjects (0.2 ± 0.05 ng/ml, p < 0.01) (Figure 1A). In contrast, patients with mild asthma released higher LXA4 concentrations (1.3 ± 0.1 ng/ml) than those with severe asthma (0.8 ± 0.1 ng/ml, p < 0.0001) and control subjects (0.1 ± 0.05 ng/ml, p < 0.05) (Figure 1B).



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  		Figure 1. IL-8 and LXA4 concentrations in induced sputum. Supernatants of induced sputum from patients with mild (n = 7) and severe asthma (n = 9) and control subjects (n = 6) were collected. IL-8 and LXA4 concentrations in supernatants of induced sputum from these subjects are reported in A and B, respectively. IL-8 and LXA4 concentrations were assessed by ELISA. The results were analyzed using a Kruskal Wallis test with a post hoc test and, values are expressed as means ± SEM (ng/ml). Positive correlation between IL-8 and LXA4 released in induced sputum from patients with mild asthma was analyzed with a nonparametric Spearman test (C). The correlation coefficient is indicated ({rho} = 0.82, p = 0.02).

 
There was a significant correlation between IL-8 and LXA4 concentrations in supernatants of induced sputum in patients with mild asthma ({rho} = 0.82, p = 0.02) (Figure 1C). In contrast, no such correlation was observed for severe asthmatics ({rho} = 0.1, p = 0.7).

Effect of LX on Cytokine Release
IL-8 was measured in the supernatants of PBMC isolated from the two groups of subjects with asthma and cultured for 24 hours (Figure 2A) . The concentration of IL-8 released by PBMC of patients with severe asthma (n = 10) was significantly higher than that of patients with mild asthma (n = 10) (44.7 ± 1.8 ng/ml versus 11.2 ± 2.9 ng/ml, p < 0.05).



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  		Figure 2. Release of IL-8 by PBMC and effects of LXA4 and LXB4 on this IL-8 release. (A) Basal IL-8 released by PBMC from patients with mild (n = 10) and severe (n = 10) asthma. PBMC were incubated at a concentration of 106 cells/ml in supplemented Dulbecco modified Eagle medium for 24 hours at 37° C. IL-8 concentrations in supernatants were measured by ELISA. Data are expressed as nanograms per milliliter and are shown as means ± SEM. The results were analyzed using a nonparametric Mann–Whitney test, and a p value of less than 0.05 is indicated. PBMC from patients with mild (n = 10, B) and severe (n = 10, C) asthma were treated with different concentrations (0.1, 1, 10, 100, and 1,000 nmol/L) of LXA4 (open circles) and LXB4 (filled circles) for 24 hours. After 24 hours, IL-8 was quantified by ELISA in supernatants. The results are expressed as means ± SEM of the percentage of inhibition and were analyzed using Student's t test. Results obtained with p values less than 0.05 (*), less than 0.01 ({dagger}), and less than 0.001 ({ddagger}) are indicated.

 
In vitro, LXA4 and LXB4 treatment of PBMC from these two groups of patients for 24 hours inhibited IL-8 release at nanomolar concentrations (Figure 2B). In PBMC from patients with mild asthma (left panel), LXA4 significantly inhibited IL-8 release at all concentrations except 1,000 nM. LXA4 maximal inhibition was obtained at 1 nM (29.4 ± 9.7%, p < 0.01), whereas in PBMC from patients with severe asthma (right panel), maximal inhibition by LXA4 was obtained at 100 nM (41.5 ± 7.6%, p < 0.001). A 1,000-nM LXA4 concentration had a stimulatory effect on IL-8 release by PBMC from patients with mild asthma (41.9 ± 20.5%, p < 0.05), whereas this effect was not seen in patients with severe asthma.

LXB4 inhibited IL-8 release with maximal inhibition at 10 nM for mild asthmatics (28.9 ± 8.8%, p < 0.01) (left panel) and at 100 nM for severe asthmatics (36.4 ± 6.3%, p < 0.001) (right panel).

We found that LXA4 was more effective in severe asthma than in mild asthma. Indeed, LXA4 inhibition reached 40% in severe asthma, whereas in mild asthma it was near 20% at 100 nM (p < 0.05).

ALXR mRNA Concentrations
To evaluate ALXR mRNA expression in PBMC, reverse transcription–PCR (RT-PCR) was performed with specific primers for human PBMC ALXR and HPRT cDNA. Expression of the the HPRT housekeeping gene was determined as an internal control for RT-PCR efficiency. A representative electrophoretic analysis of PCR products obtained with PBMC from control subjects and patients with mild and severe asthma is shown in Figure 3A . Densitometric scanning of the data indicated that ALXR mRNA expression in PBMC was not significantly different for patients with asthma and control subjects (Kruskal Wallis, p = 0.1).



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  		Figure 3. ALXR mRNA expression in PBMC from control subjects (n = 6) and patients with mild (n = 9) and severe (n = 9) asthma. (A) Representative results of RT-PCR for ALXR and HPRT mRNA in PBMC are given: control subjects (lanes 1 and 2) and patients with mild (lanes 3 and 4) and severe (lanes 5 and 6) asthma. M is the 100-bp DNA ladder. (B) PCR products were semi-quantified by densitometric scanning and normalized relative to the amount of HPRT. The results were analyzed using a nonparametric Kruskal Wallis test and are expressed as ALXR/HPRT ratios.

 
Effect of PTX on LX-Inhibited IL-8 Release
Pretreatment of PBMC from patients with mild (n = 3) and severe asthma (n = 3) with PTX reversed the LXA4- and LXB4-inhibited IL-8 released by these cells, with no effect on the response to dexamethasone (Figure 4) .



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  		Figure 4. PTX reverses LXA4- and LXB4- inhibited IL-8 release. PBMC from patients with mild (n = 3) and severe (n = 3) asthma were incubated with PTX (2 µg/ml) for 1 hour. The cells were incubated with vehicle (V, medium alone), Dex (Dexamethasone,100 nM) as control experiment, LXA4 (100 nM), or LXB4 (100 nM) for 24 hours at 37° C. IL-8 concentrations were measured in supernatants by ELISA. The results were analyzed using Student's t test, and values are expressed as means ± SEM of the percentage of IL-8 release, compared with the vehicle (100% release). Results obtained with p values less than 0.01 ({dagger}) are indicated.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The present study confirms that patients with severe asthma present a persistent inflammation characterized by IL-8 overexpression detected either in supernatants of induced sputum or in supernatants of PBMC. Moreover, it was demonstrated that LX were present endogenously in the supernatants of induced sputum, in a markedly increased manner in untreated patients with mild asthma. Interestingly, a positive correlation between IL-8 and LXA4 was found only in patients with mild asthma. We showed that LXA4 and LXB4 inhibited IL-8 released by PBMC from patients with mild and severe asthma. Moreover, PBMC from patients with asthma expressed ALXR mRNA amounts. Finally, we demonstrated that LX exert their action via a G protein-coupled receptor, as assessed by the experiment in the presence of PTX.

It has been observed previously that LXA4 is present in vivo in bronchoalveolar lavage fluids from patients with respiratory diseases, including those with asthma (22). In our present study, we were able to detect LXA4 in the supernatants of induced sputum in the two groups of patients and in control subjects. We have shown previously that human alveolar macrophages and blood PMN from subjects with asthma synthesized higher concentrations of LX than did normal subjects (3, 23). In a recent study, we have demonstrated that blood neutrophils from severe asthmatics produced less LX than did those from untreated patients with asthma and control subjects showing decreased 5-LO activity (10). Interestingly, patients with severe asthma presented lower LXA4 concentrations in supernatants of induced sputum than did patients with mild asthma. Moreover, we highlighted a correlation between IL-8 and LXA4 concentrations found in the supernatants of induced sputum only for mild asthmatics, thus demonstrating that the increase in inflammatory mediators might be counterbalanced by an increase in antiinflammatory LX synthesized. In contrast, this correlation was no longer present in patients with severe asthma or in control subjects.

Higher concentrations of IL-8 were detected in supernatants of induced sputum from patients with severe asthma as compared with patients with mild asthma and control subjects. In the same way, we confirmed previous findings showing that PBMC from patients with severe asthma released higher IL-8 concentrations than those of patients with mild asthma. At nanomolar concentrations, when incubated with exogenous LXA4 and LXB4, this IL-8 released by PBMC from patients with mild and severe asthma was inhibited. We showed that LXA4 was more effective in severe asthma than in mild asthma. Indeed, LXA4 inhibition reached 40% in severe asthma, whereas in mild asthma it was near 20% at 100 nM. It was reported previously that native LX were rapidly metabolized by cells, particularly by monocytes (35–38). We suggest that the persistent inflammatory state in severe asthma enhances the activity of endogenous LX. Inflammation may modify the metabolism of LX by preventing the generation of inactive compounds to allow a better LX action in severe asthma.

The expression of specific high affinity ALXR is required for the LXA4 antiinflammatory effect (39). This receptor has been sequenced in human PMN and monocytes (13, 14). The present results demonstrated that PBMC from patients with asthma expressed the ALXR, and we did not find any difference in ALXR mRNA expression among the three groups. ALXR appears to be coupled to a PTX-sensitive G-protein in monocytes (14) and in neutrophils (12) because LXA4 responses in these cells were PTX-sensitive. PTX binds to ADP-ribosylate Gi/o containing heterodimeric G proteins and thereby inhibits dissociation of functional {alpha} and ß{gamma} subunits (15). In our study, we showed that the inhibitory effect of LXA4 on IL-8 released by PBMC from subjects with asthma was mediated via ALXR because this LXA4 response was reversible by PTX pretreatment. IL-8 inhibition by LXB4 was also reversed by this PTX pretreatment. This LXB4 effect might be mediated via a G protein–coupled receptor that has not yet been identified and sequenced because LXB4 does not bind the ALXR (40). In contrast, the IL-8 release inhibition in PBMC from the two goups of patients with asthma persisted with PTX pretreatment in response to dexamethasone. The effect of this glucocorticoid analog is mediated via its specific cytoplasmic receptor, the glucocorticoid receptor that is not coupled to a G protein (16).

In conclusion, our results indicate that persitent inflammation in severe asthma is also associated with a possible deficiency in antiinflammatory mediators such as LX. Further, LX appear to be involved in controlling both acute and chronic inflammatory processes, as suggested by their inhibiting role on IL-8 released by PBMC in mild and severe asthma. Finally, we have shown that this inflammation may also act in favor of its resolution mediated by specific receptor in asthma.


   Acknowledgments
 
Supported by CIFRE research grant 99679 and by grant AOI 1995 UF7515 from the DRC of CHU of Montpellier.


   FOOTNOTES
 
This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Received in original form January 29, 2002; accepted in final form March 18, 2002


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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