The Journal of Allergy and Clinical Immunology
Volume 114, Issue 6 , Pages 1353-1358, December 2004

Urinary eicosanoid and tyrosine derivative concentrations in patients with vasculitides

  • Noritaka Higashi, MD, PhD

      Affiliations

    • From the Clinical Research Center, National Sagamihara Hospital, Sagamihara, Kanagawa
    • Third Department of Internal Medicine, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima
    • Corresponding Author InformationReprint requests: Noritaka Higashi, MD, Scheeles väg1, PO Box 287, National Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
    • ,
  • Haruhisa Mita, PhD

      Affiliations

    • From the Clinical Research Center, National Sagamihara Hospital, Sagamihara, Kanagawa
    • ,
  • Masami Taniguchi, MD, PhD

      Affiliations

    • From the Clinical Research Center, National Sagamihara Hospital, Sagamihara, Kanagawa
    • ,
  • Naomi Turikisawa, MD, PhD

      Affiliations

    • From the Clinical Research Center, National Sagamihara Hospital, Sagamihara, Kanagawa
    • ,
  • Ai Higashi, MD

      Affiliations

    • From the Clinical Research Center, National Sagamihara Hospital, Sagamihara, Kanagawa
    • Third Department of Internal Medicine, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima
    • ,
  • Yoshinori Ozawa, MD, PhD

      Affiliations

    • From the Clinical Research Center, National Sagamihara Hospital, Sagamihara, Kanagawa
    • ,
  • Shigeto Tohma, MD, PhD

      Affiliations

    • From the Clinical Research Center, National Sagamihara Hospital, Sagamihara, Kanagawa
    • ,
  • Kimiyoshi Arimura, MD, PhD

      Affiliations

    • Third Department of Internal Medicine, Kagoshima University School of Medicine, Sakuragaoka, Kagoshima
    • ,
  • Kazuo Akiyama, MD

      Affiliations

    • From the Clinical Research Center, National Sagamihara Hospital, Sagamihara, Kanagawa

Received 23 April 2004; received in revised form 3 August 2004; accepted 20 September 2004.

Sagamihara, Kanagawa, and Kagoshima, Japan

Article Outline

Background

Vasculitides are classified on the basis of the type of cell involved, namely, eosinophilic vasculitides such as Churg-Strauss syndrome (CSS) and noneosinophilic vasculitides. However, knowledge on inflammatory mediators and oxidative tissue damage associated with vasculitides is insufficient.

Objective

We measured the urinary concentrations of inflammatory mediators and tyrosine derivatives to assess biomarkers associated with the pathophysiology of vasculitides.

Methods

Urine was collected from 9 patients with CSS during acute exacerbation and during clinical remission, 24 patients with rheumatoid arthritis in stable condition, and 8 patients with vasculitis diseases (VDs) during acute exacerbation. Leukotriene E4 (LTE4), 9α,11β prostaglandin F2, and eosinophil-derived neurotoxin (EDN) concentrations were determined by enzyme immunoassay. 3-Bromotyrosine (BrY) and 3-chlorotyrosine (ClY) concentrations were determined by gas chromatography-mass spectrometry.

Results

The urinary LTE4, EDN, BrY, and ClY concentrations were significantly higher in the patients with CSS during acute exacerbation than in healthy control subjects and, except for urinary ClY concentration, significantly decreased during clinical remission. The urinary EDN and BrY concentrations were significantly higher in patients with CSS during acute exacerbation than in patients with VD during acute exacerbation. Only urinary LTE4 concentration was significantly different between the patients with rheumatoid arthritis in stable condition and the patients with VD during acute exacerbation.

Conclusion

Oxidative tissue damage caused by eosinophil peroxidase is a pathophysiological characteristic of eosinophil-associated diseases such as CSS. Urinary LTE4 concentration may reflect a pathophysiological event involved in eosinophilic and noneosinophilic vasculitides. Cysteinyl-leukotriene pathways are potential therapeutic targets for small-vessel vasculitides.

Key words: Churg-Strauss syndrome, vasculitides, 3-bromotyrosine, 3-chlorotyrosine, leukotriene E4

Abbreviations used: ANCA, Antineutrophil cytoplasmic autoantibody, BrY, 3-Bromotyrosine, ClY, 3-Chlorotyrosine, cr, Creatinine, CSS, Churg-Strauss syndrome, cysLT, Cysteinyl-leukotriene, EDN, Eosinophil-derived neurotoxin, EPO, Eosinophil peroxidase, HC, Healthy control, HOBr, Hypobromous acid, LT, Leukotriene, MPA, Microscopic polyangiitis, PG, Prostaglandin, RA, Rheumatoid arthritis, TA, Temporal arteritis, VD, Vasculitis disease, WG, Wegener granulomatosis

 

Eosinophils possess a wide range of biological properties. Namely, eosinophils release proteins, inflammatory cytokines, and mediators, such as eicosanoids and platelet-activating factors, and can cause tissue injury by releasing a spectrum of toxic products. Eosinophil peroxidase (EPO)1., 2., 3. also resides in a matrix of cytoplasmic granules and is one of the most abundant proteins in eosinophils.4 EPO plays a role in mediating the host-defense mechanism, such as the destruction of invading parasites and the pathological damage of host tissue by oxidizing intermediates. Briefly, activated eosinophils generate superoxide (O2−) by using a membrane-associated nicotinamide adenine dinucleotide phosphate oxidase,5 and its dismutation product, H2O2.1 By using H2O2 as a cosubstrate, EPO in eosinophils generates a halogenating oxidant, which is a potent reactive, cytotoxic, and diffusible species. Despite the fact that the plasma chloride (Cl−) concentration is 1000-fold higher than that of bromide (Br−), interestingly, the major product of the EPO-H2O2 system is hypobromous acid (HOBr): Br−+H2O2+H+ → HOBr+H2O.6 In vitro, HOBr reacts with primary amines to form N-mono-bromamines, and it converts tyrosine to 3-bromotyrosine (BrY).7., 8. Similarly, myeloperoxidase, a structurally and functionally distinct enzyme produced by neutrophils, monocytes, and certain tissue macrophages,9 also contributes to inflammatory tissue injury. Neutrophils selectively use Cl− in plasma to generate chlorinating oxidants.10., 11., 12. Thus, 3-chlorotyrosine (ClY) is considered to be a selective marker of myeloperoxidase-catalyzed oxidation, whereas BrY is that of EPO-catalyzed oxidation.13

The characteristic feature of Churg-Strauss syndrome (CSS),14., 15. an eosinophilic necrotizing vasculitis,16 is hypereosinophilia in blood and tissues, such as those of the lungs, gastrointestine, nerves, and kidneys. The extent of eosinophilia commonly reflects clinical disease activity.14., 15. Previous studies demonstrated that the seromarkers of the activation of eosinophils, such as eosinophil cationic protein and eosinophil-derived neurotoxin (EDN), can predict a relapse.17 However, measurement of these seromarkers is not applicable to patients with noneosinophilic small-vessel vasculitides, such as Wegener granulomatosis (WG) and microscopic polyangiitis (MPA). Considering the oxidative reaction-associated myeloperoxidase in the human artery,12., 18. we hypothesized that measuring both BrY and ClY may serve as a powerful method for estimating oxidative tissue damage and the relative contributions of eosinophils versus neutrophils in vivo. Furthermore, the high levels of antibody against myeloperoxidase-specific antineutrophil cytoplasmic autoantibody (ANCA) are observed in patients with myeloperoxidase-ANCA–related vasculitides such as WG and MPA.19., 20. Because ANCA-activated neutrophils can adhere to and destroy endothelial cells in vitro, ANCA is considered to inhibit the inactivation of myeloperoxidase, resulting in tissue damage.21., 22. In addition, Mayatepek and Lehmann23 demonstrated a high urinary leukotriene (LT) E4 concentration in patients with Kawasaki disease, which is the most common childhood vasculitis. However, there has been little experimental evidence to substantiate the close relationship between cysteinyl-leukotriene (cysLT) and vasculitides. According to the National Institutes of Health workshop report,24 there is no objective evidence that CSS is actually caused by LT receptor antagonists. Because there have been no comparative studies of urinary eicosanoid concentrations and clinical characteristics, we aimed to characterize the profiles of eicosanoid, BrY, and ClY concentrations in patients with systemic small-vessel vasculitides, including CSS.

Back to Article Outline

Methods 

Subjects 

The subjects of this study were 9 patients with CSS (age range, 27-75 years; mean age, 51.8 years; 2 male and 7 female), 8 patients with vasculitis diseases (VDs) during acute exacerbation (age range, 50-77 years; mean age, 66.0 years; 2 male and 6 female), 24 patients with rheumatoid arthritis (RA) in a clinically stable condition (age range, 39-77 years; mean age, 60.1 years; 6 male and 18 female), and 8 healthy control (HC) subjects (age range, 27-55 years; mean age, 37.3 years; 4 male and 4 female). CSS was diagnosed according to the 1990 American College of Rheumatology criteria and the 1992 Chapel Hill definition.25., 26. Three patients had recurrent CSS. The mean age at onset of CSS was 49.8 (Table I). Histopathological confirmations, such as necrotizing vasculitis, extravascular necrotizing granulomas, and/or hypereosinophilia in extravascular tissues, were present in all 9 patients with CSS. Clinical examinations and staging included the lung function test, chest radiography, bronchoalveolar lavage test, echocardiography, radioisotope scintigraphy, otorhinolaryngologic and neurologic examinations, and laboratory screening for ANCA.27 During the acute exacerbation of CSS, all patients with CSS showed vasculitis symptoms involving multiple organs, such as eosinophilic pneumonia and cardiopathy, in addition to peripheral hypereosinophilia (mean %, 58.1%) and mononeuritis multiplex, as shown in Table I. After intensive immunosuppressive therapies with drugs including systemic corticosteroids (n=5 with intravenous administration of 1000 mg/d methylprednisolone for 3 days; n=9 with 30-40 mg/d prednisolone), cyclosporine (n=5, 50-100 mg/d), and/or intravenous immunoglobulin27 (n=7), all 9 patients with CSS were clinically in a disease remission phase, maintained at a dose of 5 to 25 mg/d prednisolone (n=7) in addition to cyclosporine (n=4, 50-100 mg/d) at the time of follow-up examination. The mean percentage of peripheral eosinophils was 2.3%. The duration between acute exacerbation and remission was 6.1 ± 2.5 months.

Table I. Demographic characteristics of patients with CSS
Male/female sex2/7
Age, y, mean (SD)51.8 (15.2)
Age at onset, y, mean (SD)
Asthma onset42.3 (14.3)
CSS onset49.8 (14.5)
Blood eosinophil ×106/L, median (range)
During acute exacerbation6590 (2510-17,880)
During remission70 (10-700)
IgE-radioimmunosorbent test, IU/mL, median (range)467 (18-3360)
Cumulative organ involvement, n
Mononeuritis multiplex9
Lung9
Sinus7
Kidney/urinary tract7
Heart4
Skin2
Mediastinum1

The patients with VD had an acute exacerbation of vasculitis accompanied by autoimmune diseases, such as MPA,26 WG,26., 28. temporal arteritis (TA, giant-cell arteritis),29 and RA30 (Table II). The patients with VD were diagnosed on the basis of clinical and laboratory examination findings, such as the presence of ANCA (n=4) and immunocomplex C1q. Pathological vasculitis was confirmed in 5 of 8 patients. In contrast, the stable RA group, composed of 24 patients with RA in a stable condition, was a comparative control for patients with an acute exacerbation of VD. Nine patients received systemic corticosteroid (mean prednisolone dose, 4.2 mg/d), whereas 12 patients received methotrexate therapy. None of the patients had an upper respiratory tract infection in the 4 weeks preceding the study. Permission to conduct the study was obtained from the Ethics Committee of the National Sagamihara Hospital, and all of the patients who participated gave their informed consent.

Table II. Demographic characteristics of patients with VD
Male/female sex2/6
Age, y, mean (SD)66.0 (8.4)
White blood cells ×106/L9453 (3024)
Neutrophil %, mean (SD)81.0 (8.7)
Eosinophil %, mean (SD)2.1 (1.9)
C-reactive protein, mg/dL, mean (SD)9.7 (6.6)
C1q, mg/mL, median (range)∗5.0 (1.6-29.6)
Underlying diseases, n
RA3
MPA1
MPA, PSS, and Sjogren syndrome1
WG1
Mixed-connective tissue disease and RA1
TA and Behcet disease1
Cumulative vasculitis-associated symptoms, n
Mononeuritis multiplex5
Skin ulcer2
Scleritis2
RA nodule/TA nodule3/1
Pathological findings, n5
Obstructive vasculitis/necrotizing vasculitis3/2

∗n=7.

Measurements 

Spot urine was collected between 9:00 and 11:00 am from patients with CSS during acute exacerbation and during clinical remission, patients with VD during acute exacerbation, patients with stable RA, and HC subjects. In particular, in the cases of acute exacerbations of CSS and VD, urine was collected before intensive immunosuppressive therapy. We determined the urinary concentrations of LTE4 (Cayman, Ann Arbor, Mich), 9α,11β prostaglandin (PG) F2 (Cayman), which corresponds to the PGD2 metabolite, and EDN (MBL, Nagoya, Japan) by enzyme immunoassay as previously reported.31 The urinary concentrations of BrY and ClY, the selective markers of EPO-catalyzed and myeloperoxidase-catalyzed oxidations, respectively, were determined by gas chromatography-mass spectrometry by using 13C-labeled compounds as internal standards, as reported elsewhere.32 Briefly, after the addition of 13C6-BrY (50 ng) and 13C6-ClY (30 ng) to 2 mL urine, BrY and ClY were extracted with 25% methanol by using a reverse-phase column and then converted to the corresponding heptafluorobutyryl tert-butyldimethylsilyl derivatives.33., 34. BrY and ClY concentrations were determined by using Shimadzu gas chromatography-mass spectrometry QP2010 (Kyoto, Japan) equipped with a SPD-5 capillary column (15 m; 0.25-mm internal diameter; 0.25-μm film thickness; Supelco, Bellefonte, Pa) in the negative ion chemical ionization mode with methane as the reagent gas. BrY and ClY concentrations were determined by measuring the fragment ions at mass-to-charge ratio (m/z) 489.10 for endogenous compounds and m/z 495.15 for the internal standards. Urinary LTE4, 9α,11βPGF2, EDN, BrY, and ClY concentrations were normalized to urinary creatinine (cr) concentration.

Analysis of data 

Demographic characteristics are expressed as means ± SDs. The urinary eicosanoid, EDN, BrY, and ClY concentrations are expressed on a log scale in the figures. These urinary concentrations in the 4 groups (CSS during acute exacerbation, VD during acute exacerbation, stable RA, and HC groups) were first compared by using the Kruskal-Wallis test. When a significant difference was found, the Mann-Whitney U test with the Bonferroni correction for comparison between groups was performed. The urinary concentrations of the 5 biomarkers in CSS patients during acute exacerbation and clinical remission were compared by using the Wilcoxon t test. Relationships were analyzed by using the Spearman rank correlation test. P values of less than .05 were regarded as statistically significant.

Back to Article Outline

Results 

As shown in Fig 1, the urinary LTE4 concentration was significantly higher in the patients with CSS during acute exacerbation (median, 449.6 pg/mg-cr) than in the patients with stable RA (median, 79.3 pg/mg-cr; P < .01) and the HC subjects (67.5 pg/mg-cr; P < .05). A significantly higher urinary EDN concentration was observed in the patients with CSS during acute exacerbation (2404.0 ng/mg-cr) than in the patients with VD (432.3 ng/mg-cr; P < .05), the patients with stable RA (296.7 ng/mg-cr; P < .01), and the HC subjects (94.9 ng/mg-cr; P < .05), respectively. Fig 2 shows the urinary BrY and ClY concentrations in each group. The urinary BrY concentration was significantly higher in the patients with CSS during acute exacerbation (182.6 ng/mg-cr) than in the patients with stable RA (36.8 ng/mg-cr; P < .01) and the HC subjects (25.2 ng/mg-cr; P < .05). The urinary ClY concentration was significantly higher in the patients with CSS during acute exacerbation (6.1 ng/mg-cr; P < .05), the patients with VD during acute exacerbation (9.2 ng/mg-cr; P < .05) and the patients with stable RA (4.7 ng/mg-cr; P < .05) than in the HC subjects (1.2 ng/mg-cr). No significant difference in urinary 9α,11βPGF2 concentration was observed among the 4 groups (data was not shown). Next, we examined the correlation between these urinary parameters and the involvement of vasculitis. As shown in Fig 1, Fig 2, there were significant differences in urinary LTE4, EDN, and BrY concentrations in the patients with CSS during acute exacerbation and clinical remission (median, for LTE4, 449.6 pg/mg-cr vs 91.2 pg/mg-cr; P < .01; for EDN, 2404.0 ng/mg-cr vs 151.7 ng/mg-cr; P < .01; for BrY, 182.6 ng/mg-cr vs 44.4 ng/mg-cr; P < .05). Only urinary LTE4 concentration was significantly different between the patients with stable RA and the patients with VD during acute exacerbation (median, 79.3 pg/mg-cr vs 434.0 pg/mg-cr; P < .01). No correlation was found among these 5 urinary markers in any of the 4 groups.

  • View full-size image.
  • Fig 1. 

    Urinary LTE4 (A) and EDN (B) concentrations in each group. Urinary concentrations are expressed by using the log scale. Patients with CSS, VD, and RA and HC subjects are denoted by closed squares, closed triangles, open triangles, and open circles, respectively. Horizontal bars indicate medians. ∗P < .05; †P < .01.

Back to Article Outline

Discussion 

Leukotriene E4 has been identified as a major metabolite of LTC4, and urinary LTE4 concentration is now considered the most appropriate analytical parameter for monitoring the endogenous synthesis of cysLTs.35 In this study, we demonstrated for the first time that urinary LTE4 concentration was significantly higher in patients with CSS during acute exacerbation than in HC subjects, and significantly decreased during clinical remission. It is most interesting to note that the increased urinary LTE4 concentration in patients with VD during acute exacerbation was observed despite relatively low EDN concentrations. Recent studies have demonstrated a close relationship between cysLTs and vascular events. Sjöström et al36 demonstrated that microsomal glutathione S-transferase 2, a distant homologue of LTC4 synthase, is a critical enzyme present in vascular walls for LTC4 biosynthesis, originating from the transfer of LTA4 from granulocytes to endothelial cells. In addition, an increased urinary LTE4 concentration was observed in patients with ischemic heart diseases.37., 38., 39. Taking these findings together, transcellular biosynthesis among mononuclear cells and endothelial cells plays an important role in the cysLT overproduction in vasculitides. Aspirin intolerance is also characterized by a cysLT overproduction profile.40., 41., 42. In particular, the clinical features of CSS are quite similar to those of the aspirin intolerance phenotype—namely, bronchial asthma, eosinophilic sinusitis, and hypereosinophilia. We previously demonstrated that basal urinary LTE4 concentration in patients with asthma is higher than that in HC subjects, and that basal urinary LTE4 concentration in asthmatic patients with eosinophilic sinusitis is higher than that in asthmatic patients without eosinophilic sinusitis.40 In addition, we preliminarily confirmed in this study that markedly high urinary LTE4 concentrations (167.6, 188.3, and 199.0 pg/mg-cr) were observed in 3 patients with nonvasculitic eosinophil diseases (acute eosinophilic pneumonia, episodic eosinophilic angioedema, and bronchial asthma with hypereosinophilia). However, despite markedly high percentages of blood eosinophils (mean, 34.6%), the extents of increase in urinary LTE4 concentrations in these 3 patients with nonvasculitic eosinophil diseases were relatively smaller than in patients with CSS. Thus, particularly in CSS, eosinophilic vasculitides may be involved in cysLT overproduction in addition to eosinophilic pneumonia and sinusitis. Transcellular biosynthesis among endothelial cells and LTC4 synthase–positive cells, including eosinophils, plays a key role in the mechanism underlying cysLT production in CSS. The vicious cycle, in which cysLTs promote the progenitor effect of LTC4-producing cells,43 possibly contributes to the further increased production of cysLTs in patients with an acute exacerbation of vasculitides. At least, this study demonstrated that urinary LTE4 concentration as a new biomarker determined by a noninvasive methodology possibly contributes to the early diagnosis of small-vessel vasculitides.

In this study, we determined the urinary concentrations of 2 halogenated oxidation products—that is, BrY and ClY. BrY is considered a candidate marker of eosinophil activation,13., 32. ClY of neutrophil and monocyte activation. BrY and ClY concentrations in biological samples such as bronchoalveolar lavage fluid13., 44. and sputum45 have been determined. Thus, we hypothesized that the adaptation of this methodology is expected to identify oxidative tissue damage and the involvement of specific inflammatory cells in vasculitides and hypereosinophilia.46., 47. In the patients with CSS, the urinary BrY concentration significantly increased during acute exacerbation and decreased during clinical remission. We previously demonstrated the significantly higher urinary BrY and ClY concentrations in patients with asthma than in the HC subjects.32 Similarly, 3 patients with nonvasculitic eosinophil diseases described previously also showed high urinary BrY concentrations (97.4, 122.9, and 62.0 ng/mg-cr). Thus, these findings suggest that the oxidative tissue damage caused by activated eosinophils is a pathophysiological characteristic of eosinophil-associated diseases such as bronchial asthma and CSS. In contrast, we also analyzed the time course of the concentrations of urinary tyrosine derivatives in 2 patients with severe anaphylactic shock. This additional analysis showed normal urinary tyrosine derivative concentrations despite marked increases in urinary 9α,11βPGF2 and LTE4 concentrations during severe anaphylactic shock, suggesting that the effect of activated mast cells on urinary tyrosine derivative concentration (data not shown) is negligible or limited. Moreover, these results strongly suggest that BrY and ClY are preferentially produced by activated eosinophils and neutrophils/monocytes, respectively. Interestingly, 2 deceased patients with VD showed the highest concentration of urinary BrY (145.6 and 196.2 ng/mg-cr), and 1 of them also had methotrexate-induced pneumonitis.48 There is clear evidence linking eosinophils and methotrexate-induced lung injury. The blood and tissue eosinophilia are often found in patients with methotrexate-induced pneumonitis.49 Considering that the patients with VD in our study are heterogeneous, further investigations of a large number of patients with VD are required to determine whether urinary BrY concentration may be a useful prognostic predictor of vasculitides and methotrexate-induced pneumonitis. There was no significant difference in urinary ClY concentration among the patients with RA, VD, and CSS, suggesting that urinary ClY concentration may be a less sensitive biochemical indicator of noneosinophilic oxidative tissue damage. Urinary BrY and ClY concentrations may not be directly associated with the pathogenesis of vasculitides. However, we must consider that the stable and major metabolites of BrY and ClY in urine have not yet been elucidated. Other candidate biomarkers for oxidative tissue damage in vasculitides may be total nitrite and nitrate (NO2−+NO3−) concentration50 and 3-nitro-4-hydroxyphenyacetic acid concentration51 in urine.

In conclusion, although urinary LTE4 concentration failed to discriminate these 2 eosinophilic and noneosinophilic vasculitides, urinary LTE4 concentration may be used as a sensitive biomarker for monitoring the pathophysiological events involved in vasculitides. These data suggest that cysLT pathways may be new therapeutic targets for small-vessel vasculitides. In addition, we demonstrated for the first time that oxidative tissue damage caused by activated eosinophils is a pathophysiological characteristic of eosinophil-associated allergic diseases such as bronchial asthma and CSS.

Back to Article Outline

References 

  1. Jong EC, Henderson WR, Klebanoff SJ. Bactericidal activity of eosinophil peroxidase. J Immunol. 1980;124:1378–1382
  2. Ten RM, Pease LR, McKean DJ, Bell MP, Gleich GJ. Molecular cloning of the human eosinophil peroxidase: evidence for the existence of a peroxidase multigene family. J Exp Med. 1989;169:1757–1769
  3. Sakamaki K, Tomonaga M, Tsukui K, Nagata S. Molecular cloning and characterization of a chromosomal gene for human eosinophil peroxidase. J Biol Chem. 1989;264:16828–16836
  4. Carlson MG, Peterson CG, Venge P. Human eosinophil peroxidase: purification and characterization. J Immunol. 1985;134:1875–1879
  5. Klebanoff SJ, Locksley RM, Jong EC, Rosen H. Oxidative response of phagocytes to parasite invasion. Ciba Found Symp. 1983;99:92–112
  6. Weiss SJ, Test ST, Eckmann CM, Roos D, Regiani S. Brominating oxidants generated by human eosinophils. Science. 1986;234:200–203
  7. Thomas EL, Bozeman PM, Jefferson MM, King CC. Oxidation of bromide by the human leukocyte enzymes myeloperoxidase and eosinophil peroxidase: formation of bromamines. J Biol Chem. 1995;270:2906–2913
  8. Wu W, Chen Y, d'Avignon A, Hazen SL. 3-Bromotyrosine and 3,5-dibromotyrosine are major products of protein oxidation by eosinophil peroxidase: potential markers for eosinophil-dependent tissue injury in vivo. Biochemistry. 1999;38:3538–3548
  9. Podrez EA, Abu-Sound HM, Hazen SL. Myeloperoxidase-generated oxidants and atherosclerosis. Free Radic Biol Med. 2000;28:1717–1725
  10. Weiss SJ, Klein R, Slivka A, Wei M. Chlorination of taurine by human neutrophils: evidence for hypochlorous acid generation. J Clin Invest. 1982;70:598–607
  11. Foote CS, Goyne TE, Lehrer RI. Assessment of chlorination by human neutrophils. Nature. 1983;301:715–716
  12. Hazen SL, Hsu FF, Mueller DM, Crowley JR, Heinecke JW. Human neutrophils employ chloride gas as an oxidant during phagocytosis. J Clin Invest. 1996;98:1283–1289
  13. Wu W, Samoszuk MK, Comhair SA, Thomassen MJ, Farver CF, Dweik RA, et al. Eosinophils generate brominating oxidants in allergen-induced asthma. J Clin Invest. 2000;105:1455–1463
  14. Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine. 1984;63:65–81
  15. Guillevin L, Cohen P, Gayraud M, Lhote F, Jarrousse B, Casassus P. Churg-Strauss syndrome: clinical study and long-term follow-up of 96 patients. Medicine. 1999;78:26–37
  16. Jennette JC, Wilkman AS, Falk RJ. Anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and vasculitis. Am J Pathol. 1989;35:921–930
  17. Schmitt WH, Csernok E, Kobayashi S, Klinkenborg A, Reinhold-Keller E, Gross WL. Churg-Strauss syndrome: serum markers of lymphocyte activation and endothelial damage. Arthritis Rheum. 1998;41:445–452
  18. Hazen SL, Heinecke JW. 3-Chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima. J Clin Invest. 1997;99:2075–2081
  19. van der Woude FJ, Rasmussen N, Lobatto S, Wiik A, Permin H, van Es LA, et al. Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener's granulomatosis. Lancet. 1985;1:425–429
  20. Falk RJ, Jenette JC. Anti-neutrophil cytoplasmic antibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotising and crescenteric glomerulonephritis. N Engl J Med. 1988;318:1651–1657
  21. Savige J, Gillis D, Benson E, Davies D, Esnault V, Falk RJ, et al. International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic Antibodies (ANCA). Am J Clin Pathol. 1999;111:507–513
  22. Sundy JS, Haynes BF. Pathogenic mechanisms of vessel damage in vasculitis syndromes. Rheum Dis Clin North Am. 1995;21:861–881
  23. Mayatepek E, Lehmann WD. Increased generation of cysteinyl leukotrienes in Kawasaki disease. Arch Dis Child. 1995;72:526–527
  24. Weller PF, Plaut M, Taggart V, Trontell A. The relationship of asthma therapy and Churg-Strauss syndrome: NIH workshop summary report. J Allergy Clin Immunol. 2001;108:175–183
  25. Masi AT, Hunder GG, Lie JT, Michel BA, Bloch DA, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum. 1990;33:1094–1100
  26. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitis: proposal of an International Consensus Conference. Arthritis Rheum. 1994;37:187–192
  27. Tsurikisawa N, Taniguchi M, Saito H, Himeno H, Ishibashi A, Suzuki S, et al. Treatment of Churg-Strauss syndrome with high-dose intravenous immunoglobulin. Ann Allergy Asthma Immunol. 2004;92:80–87
  28. Leavitt RY, Fauci AS, Bloch DA, Michel BA, Hunder GG, Arend WP, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthritis Rheum. 1990;33:1101–1107
  29. Hunder GG, Bloch DA, Michel BA, Stevens MB, Arend WP, Calabrese LH, et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum. 1990;33:1122–1128
  30. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–324
  31. Higashi N, Taniguchi M, Mita H, Osame M, Akiyama K. A comparative study of eicosanoid concentration in sputum and urine in the patients with aspirin-intolerant asthma. Clin Exp Allergy. 2002;32:1484–1490
  32. Mita H, Higashi N, Taniguchi M, Higashi A, Kawagishi Y, Akiyama K. Urinary 3-bromotyrosine and 3-chlorotyrosine concentrations in asthmatic patients: lack of increase in 3-bromotyrosine concentration in urine and plasma proteins in aspirin-induced asthma after aspirin challenge. Clin Exp Allergy. 2004;34:931–938
  33. Frost MT, Halliwall B, Moore KP. Analysis of free and protein-bound nitrotyrosine in human plasma by a gas chromatography/mass spectrometry method that avoids nitration artifacts. Biochem J. 2000;345:453–458
  34. Gaut JP, Byun J, Tran HD, Heinecke JW. Artifact-free quantification of free 3-chlorotyrosine, bromotyrosine, and 3-nitrotyrosine in human plasma by electron capture-negative chemical ionization gas chromatography mass spectrometry and liquid chromatography-electrospray ionization tandem mass spectrometry. Anal Biochem. 2002;300:252–259
  35. Kumlin M. Measurements of leukotrienes in the urine: strategies and applications. Allergy. 1997;52:124–135
  36. Sjöström M, Jakobsson PJ, Heimburger M, Palmblad J, Haeggström JZ. Human umbilical vein endothelial cells generate leukotriene C4 via microsomal glutathione S-transferase type 2 and express the CysLT1 receptor. Eur J Biochem. 2001;268:2578–2586
  37. Sampson AP. Leukotrienes in cardiovascular disease. Clin Exp Allergy Rev. 2001;1:170–174
  38. Brezinski DA, Nesto RW, Serhan CN. Angioplasty triggers intracoronary leukotrienes and lipoxin A4: impact of aspirin therapy. Circulation. 1992;86:56–63
  39. Szczeklik A, Nizankowska E, Mastalerz L, Bochenek G. Myocardial ischemia possibly mediated by cysteinyl leukotrienes. J Allergy Clin Immunol. 2002;109:572–573
  40. Higashi N, Taniguchi M, Mita H, Kawagishi Y, Ishii T, Higashi A, et al. Clinical features of asthmatic patients with increased urinary leukotriene E4 excretion (hyperleukotrienuria): involvement of chronic hyperplastic rhinosinusitis with nasal polyposis. J Allergy Clin Immunol. 2004;113:277–283
  41. Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis, diagnosis and management. J Allergy Clin Immunol. 2003;111:913–921
  42. Mastalerz L, Setkowicz M, Sanak M, Szczeklik A. Hypersensitivity to aspirin: common eicosanoid alterations in urticaria and asthma. J Allergy Clin Immunol. 2004;113:771–775
  43. Laitinen LA, Laitinen A, Haahtela T, Vilkka V, Spur BW, Lee TH. Leukotriene E4 and granulocytic infiltration into asthmatic airways. Lancet. 1993;341:989–990
  44. MacPherson JC, Comhair SA, Erzurum SC, Klein DF, Lipscomb MF, Kavuru MS, et al. Eosinophils are a major source of nitric oxide-derived oxidants in severe asthma: characterization of pathways available to eosinophils for generating reactive nitrogen species. J Immunol. 2001;166:5763–5772
  45. Aldridge RE, Chan T, van Dalen CJ, Senthilmohan R, Winn M, Venge P, et al. Eosinophil peroxidase produces hypobromous acid in the airways of stable asthmatics. Free Radic Biol Med. 2002;33:847–856
  46. Holgate ST. The epidemic of allergy and asthma. Nature. 1999;402:B2–B4
  47. Weller PF. Eosinophils: structure and functions. Curr Opin Immunol. 1994;6:85–90
  48. Sato E, Camhi SL, Koyama S, Robbins RA. Methotrexate stimulates lung fibroblasts and epithelial cells to release eosinophil chemotactic activity. J Rheumatol. 2001;28:502–508
  49. Cooper JA, White DA, Matthay RA. Drug-induced pulmonary disease, part 1: cytotoxic drugs. Am Rev Respir Dis. 1986;133:321–340
  50. Evereklioglu C, Özbek E, Çekmen M, Mehmet N, Duygulu N, Ozkiris A, et al. Urinary nitric oxide levels are increased and correlated with plasma concentrations in patients with Behçet's disease: is it a new urinary activity marker?. Nephrology (Carlton). 2003;8:231–238
  51. Mani AR, Pannala AS, Orie NN, Ollosson R, Harry D, Rice-Evans CA, et al. Nitration of endogenous para-hydroxyphenylacetic acid and the metabolism of nitrotyrosine. Biochem J. 2003;374:521–527

PII: S0091-6749(04)02482-0

doi:10.1016/j.jaci.2004.09.027

The Journal of Allergy and Clinical Immunology
Volume 114, Issue 6 , Pages 1353-1358, December 2004

Article Tools

* Image Usage & Resolution