Eotaxin in induced sputum of asthmatics: relationship with eosinophils and eosinophil cationic protein in sputum

BACKGROUND: Eosinophilic inflammation is a crucial aspect of allergic diseases such as bronchial asthma. An eosinophil-active chemokine, eotaxin, may play a role in the pathogenesis of the tissue eosinophilia accompanying asthma. METHODS: Induced sputa were obtained from 53 patients with atopic asthma and six healthy subjects, and the concentration of eotaxin in the sputum was measured by ELISA. We investigated whether the sputum content of eotaxin is related to 1) asthma status or corticosteroid therapy, and 2) other sputum indices, including percentage of eosinophils and concentration of eosinophil cationic protein (ECP). RESULTS: The patients with stable or unstable asthma showed significantly higher concentrations of sputum eotaxin than the normal controls. The level of sputum eotaxin demonstrated a positive correlation with the percentage of eosinophils in stable asthmatics not receiving corticosteroid therapy, but not in stable patients treated with corticosteroids, or in unstable patients. Sputum eotaxin demonstrated a positive correlation with ECP in asthmatic patients who were either in a stable state or not receiving steroid therapy. CONCLUSIONS: The elevated level of eotaxin detected in association with increased eosinophils and ECP in the sputum of asthmatics suggests that eotaxin is involved in the pathogenesis of eosinophilic airway inflammation. The relationship of eotaxin to airway eosinophilia may be modified by the stability status of asthma and corticosteroid therapy.     

Changes in serum eotaxin and eosinophil cationic protein levels, and eosinophil count during treatment of childhood asthma.

BACKGROUND AND PURPOSE: Increased serum levels of eotaxin are related to the severity of asthma in adults. There are limited data on the effects of oral corticosteroids and inhaled corticosteroid therapy on serum levels of eotaxin and eosinophil cationic protein (ECP) and peripheral blood eosinophil counts (ECs) in pediatric asthma patients. We investigated prospectively the changes in eotaxin and ECP serum levels and peripheral blood ECs after administering oral corticosteroids and then inhaled corticosteroids plus long-acting beta2 agonist treatment in pediatric patients. METHODS: Serum samples of 20 pediatric patients with mild-to-moderate asthma were collected before treatment, after 5-7 days of oral prednisolone treatment, and after 1-2 months of inhaled fluticasone plus salmeterol treatment. Peak expiratory flow was used as the outcome index. RESULTS: Serum eotaxin levels remained the same after oral prednisolone treatment, but decreased after subsequent inhalation treatment compared with the end of oral steroid treatment (64.7 +/- 22.6 vs 85.7 +/- 36.8 pg/mL, p<0.001). The EC and serum ECP levels declined soon after oral steroid treatment, rebounding to initial levels during inhalation treatment. The decrease in ECP level was positively correlated with the decrease in ECs with oral steroid treatment (r(2) = 0.28, p=0.016). There was no correlation between changes in eotaxin levels and peak expiratory flow. CONCLUSIONS: Our data suggest that the serum eotaxin level, not peripheral blood EC or serum ECP level, declines during inhaled fluticasone plus salmeterol treatment and might serve as a surrogate marker of T helper 2 residual activity in pediatric asthma.     

Idiopathic eosinophilic esophagitis is associated with a T(H)2-type allergic inflammatory response.

BACKGROUND: Idiopathic eosinophilic esophagitis (IEE) is a chronic-inflammatory disorder of the esophagus of unknown origin. The established cornerstone of diagnosis is a dense infiltration of the esophagus with eosinophils, but neither the precise pattern of inflammatory cell infiltration nor the mechanisms that likely contribute to induction and maintenance of the inflammatory response have been described. OBJECTIVE: The intention of this study was to characterize the esophageal inflammatory infiltrate and the expression of cytokines in the esophagus in this disease. In addition, we searched for immunologic abnormalities of blood leukocytes to exclude major primary hyporeactive and hyperreactive conditions of the immune system. METHODS: Infiltration of inflammatory cells in the esophagus, stomach, and duodenum was analyzed by immunohistochemistry through use of mAbs against lineage-associated molecules. Cytokine expression was measured by ELISA and immunohistochemical analysis. Lymphocyte subpopulations in blood were determined by means of flow cytometry. RESULTS: High eosinophil infiltration into the esophageal squamous epithelium was observed in patients with IEE but not in control subjects. Interestingly, increased T-cell and mast cell numbers were also found within the epithelium in these patients. In contrast, the numbers of inflammatory cells were not increased in the stomach and duodenum in patients with IEE, suggesting a specific inflammatory process within the esophagus. Moreover, increased expression of IL-5 and TNF-alpha was observed in esophageal epithelial biopsy specimens. The distribution of lymphocyte subsets in the peripheral blood and their capacity to generate cytokines did not reflect the changes observed at the inflammatory site. CONCLUSIONS: IEE is a selective inflammatory response of the esophagus. T cells, IL-5, eosinophils, and IgE-mediated mechanisms appear to be involved, giving rise to the possibility that allergic reactions might play a role in the pathogenesis of the disease.     

Idiopathic eosinophilic esophagitis is associated with a TH2-type allergic inflammatory response

Background: Idiopathic eosinophilic esophagitis (IEE) is a chronic-inflammatory disorder of the esophagus of unknown origin. The established cornerstone of diagnosis is a dense infiltration of the esophagus with eosinophils, but neither the precise pattern of inflammatory cell infiltration nor the mechanisms that likely contribute to induction and maintenance of the inflammatory response have been described. Objective: The intention of this study was to characterize the esophageal inflammatory infiltrate and the expression of cytokines in the esophagus in this disease. In addition, we searched for immunologic abnormalities of blood leukocytes to exclude major primary hyporeactive and hyperreactive conditions of the immune system. Methods: Infiltration of inflammatory cells in the esophagus, stomach, and duodenum was analyzed by immunohistochemistry through use of mAbs against lineage-associated molecules. Cytokine expression was measured by ELISA and immunohistochemical analysis. Lymphocyte subpopulations in blood were determined by means of flow cytometry. Results: High eosinophil infiltration into the esophageal squamous epithelium was observed in patients with IEE but not in control subjects. Interestingly, increased T-cell and mast cell numbers were also found within the epithelium in these patients. In contrast, the numbers of inflammatory cells were not increased in the stomach and duodenum in patients with IEE, suggesting a specific inflammatory process within the esophagus. Moreover, increased expression of IL-5 and TNF-α was observed in esophageal epithelial biopsy specimens. The distribution of lymphocyte subsets in the peripheral blood and their capacity to generate cytokines did not reflect the changes observed at the inflammatory site. Conclusions: IEE is a selective inflammatory response of the esophagus. T cells, IL-5, eosinophils, and IgE-mediated mechanisms appear to be involved, giving rise to the possibility that allergic reactions might play a role in the pathogenesis of the disease. (J Allergy Clin Immunol 2001;108:954-61.)     

Eotaxin Increases the Expression of CD11b/CD18 and Adhesion Properties in IL5, But Not fMLP-Prestimulated Human Peripheral Blood Eosinophils

A selective recruitment of eosinophils to sites of inflammation is claimed to be controlled by regulation of cytokines, chemokines and adhesion molecules. In animal models, eotaxin has been suggested to be a potent chemokine since it in cooperation with interleukin-5 induce selective chemotaxis and infiltration of eosinophils to lung tissue after an allergen provocation. We have investigated the in vitro effect of eotaxin on human peripheral blood eosinophils with respect to CD11b/CD18 expression and adhesion properties to the matrix protein fibronectin. We did not find any effect of eotaxin per se on CD11b/CD18 expression, neither on eosinophils from healthy subjects nor from patients with asymptomatic pollen related asthma. However, eotaxin significantly upregulated the quantitative level of CD11b/CD18 and increased the adhesion to fibronectin in eosinophils from healthy subjects preincubated in vitro with interleukin-5, but not in eosinophils preincubated with fMLP. Moreover, eosinophils harvested 24 hours after an in vivo allergen inhalation provocation in asthmatics, upregulated CD11b/CD18 after in vitro incubation with eotaxin alone.     

Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis

BACKGROUND: Eosinophilic esophagitis (EE) is characterized by high numbers of eosinophils in the esophagus and epithelial hyperplasia, and is being increasingly recognized. IL-5 promotes eosinophil trafficking to the esophagus, and positively regulates eosinophil growth, activation, survival, and tissue recruitment. OBJECTIVE: We hypothesized that the humanized monoclonal IgG(1) antibody against human IL-5 (mepolizumab) may be useful in the control of EE. METHODS: An open-label phase I/II safety and efficacy study of anti-IL-5 in 4 adult patients with EE and longstanding dysphagia and esophageal strictures was conducted. Patients received 3 infusions of anti-IL-5 (750 mg intravenously monthly) without change in their current therapy. The levels of plasma IL-5, peripheral blood eosinophils, and CCR3+ cells in blood, quality of life measurements, and histological analysis of esophageal biopsies were determined before and 1 month after treatment. RESULTS: Peripheral blood eosinophilia and percent of CCR3+ cells decreased by 6.4-fold and 7.9-fold (P < .05), respectively, after anti-IL-5 treatment. Notably, mean and maximal esophageal eosinophilia decreased from 46 to 6 and from 153 to 28 eosinophils/high-power field (x400; average, 8.9-fold, P < .001, and 6-fold, P < .05), respectively. Patients reported a better clinical outcome and improved quality of life (P = .03). Therapy was generally well tolerated, and responsiveness to anti-IL-5 therapy did not correlate with plasma IL-5 levels. CONCLUSION: Anti-IL-5 therapy is associated with marked decreases in peripheral blood and esophageal eosinophilia (including the number of CCR3+ blood cells) in patients with EE and improved clinical outcomes. CLINICAL IMPLICATIONS: Anti-IL-5 is a promising therapeutic intervention for EE.     

Measurement of eotaxin (CCL11) in induced sputum supernatants: validation and detection in asthma

BACKGROUND: Induced sputum is widely used in asthma research; however, for many mediators, the detection methods have not been validated. OBJECTIVE: We sought to optimize the method of detection of eotaxin, an important chemokine acting through the CCR3 receptor on eosinophils, basophils, and T(H)2 cells. METHODS: Induced sputum from normal and asthmatic subjects was processed with dithioerythritol (DTE) or PBS; recovery of eotaxin was assessed by means of ELISA before and after spiking with recombinant eotaxin. Furthermore, the effects of removing DTE by means of ultrafiltration or the addition of protease inhibitors and high-speed centrifugation on endogenous levels and spiking recovery of eotaxin were assessed. RESULTS: Endogenous eotaxin was undetectable in DTE-processed samples, with a mean of only 30% (SD, 13%) spike recovery. DTE had no effect on the immunoassay capture antibody but dramatically reduced the detection of recombinant eotaxin. Removal of DTE from sputum before immunoassay did not improve detection, although it restored the recovery of a subsequent eotaxin spike. In contrast, PBS-processed sputum resulted in an eotaxin spike recovery of 101% (SD, 20%). Addition of protease inhibitors or high-speed centrifugation had no effect on eotaxin detection. By using this optimized protocol, eotaxin levels in PBS-processed sputum samples were found to be significantly increased in asthmatic sputum (P<.05). CONCLUSION: Measurement of eotaxin by means of immunoassay is adversely affected by DTE, possibly through irreversible denaturation of epitopes, which makes eotaxin undetectable by using the immunoassay antibody. Sputum samples should be processed into PBS for assessment of eotaxin, which is present at increased levels in asthmatic sputum.     

Interactions between eotaxin, histamine and mast cells in early microvascular events associated with eosinophil recruitment to the site of allergic skin reactions in humans

BACKGROUND: The mechanism whereby allergen induces eotaxin expression at the site of allergic inflammation is incompletely understood. Structural cells, including endothelial cells, are a major source of eotaxin. OBJECTIVE: We have investigated, in vivo and in vitro, the relationship between mast cell activation and the expression of eotaxin (eotaxin 1) by endothelial cells. METHODS: The effects of intradermal allergen challenge and histamine injection on eotaxin mRNA and protein generation were studied in atopic subjects using immunofluorescence, immunohistochemistry and in situ hybridization. Histamine-induced expression of eotaxin mRNA and protein by endothelial cells was also measured, as was histamine-induced eosinophil adhesion to cultured endothelial cells. RESULTS: A rapid increase in degranulating cutaneous mast cells, together with a concomitant increase in eosinophils, was observed 60 min after allergen challenge. This was accompanied by the appearance of immunoreactive eotaxin that peaked at 1 h around blood vessels and at 3 h within the tissue. Intradermal histamine injection produced an increase in the number of eotaxin+ cells in the tissues, which was maximal at the 3-h time-point. In vitro, endothelial cells produced eotaxin mRNA and protein product in a dose- and time-dependent fashion following incubation with histamine, an effect that was blocked by levocetirizine. Pre-incubation of endothelial cells with histamine also induced a significant increase in eosinophil adherence, an effect that was inhibited with an anti-eotaxin blocking monoclonal antibody. CONCLUSION: The antigen-induced expression of eotaxin by endothelial cells and the adherence and subsequent migration of eosinophils from the microvasculature to the tissues are rapid events partially under the control of histamine released from degranulating mast cells.     

Characterization of eosinophils and detection of eotaxin in skin chamber fluid after challenge with relevant allergen in patients with mild asthma

BACKGROUND: A selective recruitment of eosinophils to sites of allergic inflammation is suggested to be controlled by regulation of cytokines, chemokines and adhesion molecules. OBJECTIVE: The aim of this study was to examine whether allergen challenge in skin chambers, applied on patients with allergic rhinitis and mild asthma, results in a selective influx of activated eosinophils and detectable levels of cytokines/chemokines related to eosinophil recruitment, such as interleukin (IL)-5 and eotaxin. METHODS: A skin blister was induced on the volar aspect of each forearm; one contained PBS-heparin buffer (control) and the other was challenged with relevant allergen. Peripheral blood was drawn before the allergen was applied to the skin chamber, and the expression of CD9, CD11b and EG2-epitope on intracellular eosinophil cationic protein (ECP) was analysed in eosinophils. Chamber fluid was collected 8 h after allergen application and analysed for differential cell counts, expression of eosinophil activity markers, the presence of ECP, eotaxin, and IL-5. RESULTS: The number of recruited leucocytes was equal in the allergen-challenged chambers and in controls. However, the number of eosinophils was significantly increased in the allergen-challenged chambers, and elevated levels of released ECP were measured. Moreover, the eosinophils recruited were activated, as shown by increased expression of EG2 and CD11b, and decreased expression of CD9, in comparison with blood eosinophils. In the skin chamber fluids, higher levels of eotaxin were detected in the allergen-challenged chambers than in controls, but there were no detectable levels of IL-5. CONCLUSION: We have demonstrated a selective recruitment of eosinophils, and higher levels of released ECP and eotaxin, in skin chambers stimulated with allergen, as compared with control chambers. Allergen challenge in skin chambers is a useful tool for studies of eosinophil recruitment, their state of activation, and their involvement in the allergic inflammatory response.     

Increased eosinophil transmigration after nasal allergen challenge in children with allergic asthma and rhinitis

BACKGROUND: Eotaxin and interleukin-5 together provide the signal essential for eosinophil transmigration to airway tissue in allergic reactions. However, it is not known whether peripheral blood eosinophils (PBE) possess an increased transmigration capacity in vitro after allergen challenge in vivo before they leave the circulation. We aimed to determine whether PBE in cat-sensitized children have increased spontaneous and/or eotaxin-induced transmigration capacity in vitro, and to what extent allergen challenge alters this feature. METHODS: Fourteen cat-allergic children and four healthy controls underwent nasal challenge with cat-allergen. Blood samples were drawn prechallenge and at 2 h and 24 h postchallenge. We analyzed the in vitro transmigration of PBE, with and without eotaxin as a chemoattractant. We used a transmigration assay with fibronectin-coated membranes. Eosinophil cationic protein (ECP) and PBE counts were run in parallel. RESULTS: The spontaneous transmigration capacity of eosinophils in vitro was significantly higher at 2 h after allergen challenge (P < 0.01 vs. prechallenge) and returned to prechallenge levels at 24 h postchallenge (P < 0.02 vs. 2 h postchallenge). Addition of eotaxin further augmented the increased transmigration. In concordance, no accompanying changes were measured in the levels of eosinophils in blood or ECP in serum. Furthermore no spontaneous or eotaxin-induced eosinophil transmigration was detected in healthy controls. CONCLUSION: PBE possess increased spontaneous (and eotaxin-induced) capacity to transmigrate as early as 2 h after allergen challenge in allergic children, without accompanying signs of eosinophil activation in terms of increased PBE count or ECP level. This is probably due to the increased stage of activation of the eosinophil, often referred to as "priming".     

alpha4 integrin-dependent eotaxin induction of bronchial hyperresponsiveness and eosinophil migration in interleukin-5 transgenic mice

We investigated the roles of eosinophil infiltration and activation induced by the eosinophil-selective chemokine eotaxin, and of the expression of eosinophil alpha4 and beta2 integrins in causing bronchial hyperresponsiveness (BHR) in interleukin (IL)-5 CBA/Ca transgenic mice. These mice did not show BHR, despite the presence of some eosinophils in the lungs. Intratracheal mouse recombinant eotaxin (3 micrograms) did not induce BHR in wild-type mice. In IL-5 transgenic mice, eotaxin (3 and 5 micrograms) increased responsiveness at 24 h and increased eosinophils in bronchoalveolar lavage (BAL) fluid by 9.4- and 14-fold by 24 h, respectively, together with augmentation of eosinophil peroxidase activity and eosinophil infiltration in the airway submucosa. Using flow cytometry, the expression of alpha4, CD11b, and CD18 was upregulated in BAL, but not in blood, eosinophils. A rat anti-alpha4 antibody inhibited eotaxin-induced BHR and eosinophil migration and activation, but an anti-CD11b antibody had no significant effects on BHR. A combination of both antibodies was more effective. IL-5 and eotaxin synergize in the induction of BHR and airway eosinophilia, effects that are dependent on the induction of eosinophil alpha4 integrin. Expression of BHR depends on the recruitment and activation of eosinophils.     

Association of interleukin-5 and eotaxin with acute exacerbation of asthma

BACKGROUND: Airway eosinophilia is frequently observed during acute exacerbation of asthma. Interleukin-5 (IL-5) and eotaxin are directly involved in the airway eosinophilia found in persistent asthma. Interrelation between these cytokines is expected to occur in acute exacerbation of asthma. Thus, we evaluated the relevance of interaction between eotaxin and IL-5 in the airway inflammation of acute exacerbation. METHODS: We measured the number of inflammatory cells and the amount of eotaxin and IL-5 in sputum from 22 healthy subjects, 21 asthmatics with acute exacerbation and 16 patients with mild persistent asthma, and reassessed these values in 7 subjects with acute exacerbation after 7 days' treatment with systemic steroid (2 mg/kg/day). Sources of IL-5 and eotaxin were investigated by immunohistochemical staining of sputum cells of 4 cases from each group. RESULTS: Both IL-5 and eotaxin levels were higher in patients with acute exacerbation of asthma than in patients with persistent asthma and normal subjects. IL-5 and eotaxin levels were significantly correlated with eosinophil percentages in mild persistent asthma. Eotaxin staining was found mainly on macrophages and occasionally on eosinophils. Steroid treatment markedly decreased eosinophil percentages and IL-5 levels within 7 days but did not alter eotaxin levels. CONCLUSIONS: Both IL-5 and eotaxin are associated with acute exacerbation of asthma. IL-5 rather than eotaxin is effectively decreased by the inhibitory effect of steroid in acute exacerbation.     

Evidence for a role for IL-5 and eotaxin in activating and recruiting eosinophils in drug-induced cutaneous eruptions

BACKGROUND: Cutaneous drug reactions may be associated with increased numbers of eosinophils in the blood and tissue. However, the factors leading to the generation of eosinophilia have not been fully delineated. OBJECTIVE: The aim of this study was to investigate the in situ expression of IL-5, eotaxin, RANTES, monocyte chemoattractant protein 3, and IL-8 together with the appearance of eosinophils in acute cutaneous drug reactions. METHODS: Skin biopsy specimens were obtained from drug-induced maculopapular exanthems (n = 9), from normal skin of control subjects (n = 9), and from the skin of patients with psoriasis (n = 8). The in situ expression of IL-5, eotaxin, RANTES, monocyte chemoattractant protein 3, and IL-8 was analyzed by using immunohistochemistry. Furthermore, the corresponding numbers of eosinophils were determined in the blood and skin sections. RESULTS: Compared with normal skin and psoriatic skin, a significantly higher number of eosinophils was found both in the blood and tissue of patients with a drug-induced exanthem. In comparison with normal skin, immunoreactivity for IL-5 and all the chemokines was also significantly enhanced in drug-induced exanthem, whereas significant differences in psoriatic were only observed for IL-5 and eotaxin. CONCLUSION: Our data indicate that IL-5 and eotaxin may particularly contribute to the activation and recruitment of eosinophils and thereby play an important pathogenic part in the development of skin inflammation in drug-induced maculopapular exanthems.     

Increases in eotaxin‐positive cells in induced sputum from atopic asthmatic subjects after inhalational allergen challenge

BACKGROUND: Eosinophils are believed to be critical proinflammatory cells in airway mucosal damage in asthma. Eotaxin is a C-C chemokine with selective activity for eosinophils and basophils. Previous studies have shown increased expression of eotaxin in the airways of asthmatics at baseline. We aimed to investigate eotaxin expression during the late-phase reaction to allergen inhalation in atopic asthmatics. METHODS: Sputum induction was performed before and 24 h after inhalational allergen challenge in atopic asthmatics, and eotaxin protein was detected immunocytochemically. RESULTS: Thirteen patients with a mean decrease in forced expiratory volume in 1 s of 28% (+/-1.5) during the early asthmatic reaction, and 39% (+/-4.7) during the late asthmatic reaction produced sufficient sputum for study. The percentage of eosinophils in sputum was increased 24 h after allergen challenge (P<0.004), and eosinophil percentages in sputum after challenge correlated with the magnitude of the late-phase reaction (r=0.56, P=0.05). The percentage of eotaxin-positive cells increased from 12.6% (range 2-43.8) to 24.3% (8.1-47.1, P<0.005). Allergen-induced increases in eotaxin-positive cells correlated with increases in eosinophils (r=0.63, P<0.01). CONCLUSIONS: These findings suggest that eotaxin may contribute to allergen-induced recruitment of eosinophils to the airway in asthmatic subjects.     

Characterization of eosinophils in soft tissue eosinophilic granuloma

BACKGROUND: Soft tissue eosinophilic granuloma assumes the form of a poorly-demarcated painless mass, and is characterized by marked eosinophil infiltration. Although this tumor decreases in size in response to steroid therapy, it grows again after discontinuation of it, and ultimately proves intractable to treatment. We recently attempted to characterize electron-microscopically the eosinophils in the area affected by soft tissue eosinophilic granuloma. METHODS: Needle biopsy of subauricular masses was carried out before and after steroid treatment. The collected tissue was observed under an electron microscope. RESULTS: Before treatment, more than 90% of the eosinophils constituting the granulation tissue had a broken cell membrane. A number of Charcot-Leyden crystals were noted in the intercellular spaces. Following steroid treatment, more than 90% of eosinophils were intact, and Charcot-Leyden crystals were no longer observed. CONCLUSION: These findings suggest that destruction of eosinophils within granulation tissue aggravates soft tissue eosinophilic granulom.     

Response to corticosteroids in chronic bronchitis

Corticosteroid drugs are often employed in the treatment of patients with chronic bronchitis. Although some patients respond favorably to such therapy, the characteristics of such patients are not known. Twenty-four patients with chronic bronchitis were treated with prednisone 30 mg daily or placebo for one week each in a double-blind crossover study. The following were monitored before and after each treatment period: physical examination, symptoms, peripheral blood eosinophil count, sputum cell exmination, forced vital capacity (FVC), before and after isoproterenol aerosol. Seven of 24 patients had an FEV1 increase greater than 30% of the control value on prednisone but not on placebo. Blood eosinophil count was elevated (greater than or equal to 350/mm(3)) in 7 patients; 2 of these 7 improved on steroid. Sputum cell examination revealed preponderance of eosinophils in 1, and occasional clumps of eosinophils in 8. Seven of these 9 responded to steroid. Sputum but not blood eosinophilia is a good predictor of a favorable response to steroid therapy.     

Acute allergic responses induce a prompt luminal entry of airway tissue eosinophils

Traditionally, traffic and activation of eosinophils in asthmatic airways are thought to take place during the late-phase allergic reaction. The present study tests the hypothesis that when eosinophils are present in the tissue before allergen exposure, as in chronically inflamed asthmatic airways, acute anaphylactic reactions initiate an eosinophil response. Using a guinea-pig allergic model, where eosinophilia is present at baseline conditions, the traffic of resident eosinophils was examined in vivo immediately after allergen challenge. By 2 min after challenge, eosinophils had moved up to apical epithelial positions. Within 10 min, a marked migration of eosinophils into the airway lumen was demonstrated. Along with the allergen-induced egression of eosinophils, acute luminal entry of plasma proteins and eotaxin occurred. Eosinophil egression was effectively inhibited by the antiexudative drug formoterol, whereas the proexudative drug bradykinin could in naive animals evoke a prompt luminal entry of eosinophils. In conclusion, the present study demonstrates that acute allergic reactions initiate a prompt transepithelial migration of resident eosinophils. Our data further suggest that this response in part is initiated by the plasma exudation response, which may alter the transepithelial gradient of eosinophil chemoattractants including eotaxin. We propose that prompt eosinophil response is a significant component of the acute phase of allergic reactions when occurring in airways where these cells are already present in the mucosa.     

IL-13 induces eosinophil recruitment into the lung by an IL-5- and eotaxin-dependent mechanism

BACKGROUND: IL-13 induces several characteristic features of asthma, including airway eosinophilia, airway hyperresponsiveness, and mucus overproduction; however, the mechanisms involved are largely unknown. OBJECTIVE: We hypothesized that IL-13-induced inflammatory changes in the lung were dependent in part on IL-5 and eotaxin, two eosinophil-selective cytokines. METHODS: Recombinant murine IL-13 was repeatedly administered to the lung by intranasal delivery until the characteristic features of asthma developed. To analyze the role of IL-5 and eotaxin, we subjected eotaxin gene-targeted, IL-5 gene-targeted, eotaxin/IL-5-double-deficient, IL-5 transgenic, and wild-type mice of the Balb/C background to the experimental regime. RESULTS: The induction of IL-13-mediated airway eosinophilia was found to occur independently of eosinophilia in the blood or bone marrow, indicating that IL-13-induced airway inflammation is primarily mediated by local effects of IL-13 in the lung. Eosinophil recruitment into both the lung tissue and bronchoalveolar lavage fluid was markedly attenuated in IL-5-deficient mice in comparison with wild-type controls. Accordingly, IL-13 delivery to IL-5 transgenic mice resulted in a large increase in airway eosinophils in comparison with wild-type mice. Interestingly, IL-13-induced eosinophilia in the bronchoalveolar lavage fluid of eotaxin-deficient mice was not impaired; however, these same mice failed to mount a significant tissue eosinophilia in response to IL-13. Finally, IL-13-induced mucus production was not affected by the presence of IL-5 or eotaxin, suggesting that IL-13-induced mucus secretion is mechanistically dissociated from airway eosinophilia. CONCLUSION: Selective components of the IL-13-induced asthma phenotype--airway eosinophilia but not mucus secretion--are differentially regulated by IL-5 and eotaxin. IL-5 is required for IL-13 to induce eosinophilia throughout the lung, whereas eotaxin regulates the distribution of airway eosinophils.     

A case of eosinophilic cellulitis (Wells' syndrome)]

A 67-year-old man sustained a minor injury on the right hand after touching a potted plant. Several days later, he noted erythema and marked swelling on the right hand and forearm. The same lesions developed on the left hand and forearm. He also had pruritic erythema on the neck, trunk, and thighs. The initial clinical diagnosis was bacterial cellulitis and contact dermatitis. However, oral antibiotic and topical steroid therapy were not effective. Laboratory investigations revealed peripheral blood eosinophilia, elevated serum IgE level, and positive antinuclear antibody. Histopathological examination of a skin biopsy specimen showed an excessive infiltration of eosinophils and flame figures in the dermis. We diagnosed this case as eosinophilic cellulitis (Wells' syndrome). The skin lesions responded rapidly to the systemic oral steroid therapy. There has been no recurrence of eruption in 1 year of follow-up. The condition of the disease was correlated to peripheral blood eosinophil counts, and serum eosinophil cationic protein levels. However, serum interleukin-5 levels were within normal limits.