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Eosinophilic esophagitis in adults is a recently described entity occurring in young males with dysphagia, in whom esophageal biopsies show eosinophilic infiltration. This study defines the clinical and histological features of patients with eosinophilic esophagitis, distinguishing it from gastroesophageal reflux disease. Esophageal biopsies from patients with dysphagia or esophagitis were reviewed blindly, and assessed for: epithelial eosinophil counts, presence of eosinophilic microabscesses, edema, basal zone hyperplasia, lamina propria papillae elongation, eosinophils and fibrosis. Clinical and endoscopic findings were obtained. Eosinophilic esophagitis was diagnosed with epithelial eosinophils > or = 15 in > or = 2 high-power fields (hpfs) or > or = 25 in any hpf. Analysis was performed with Mann-Whitney, chi2 and ANOVA tests. Of 157 cases, 41 had eosinophilic esophagitis. Male gender (81%) and age < or = 45 (54%) were commoner in patients with eosinophilic esophagitis (P = 0.001, 0.010, respectively). Dysphagia was more common in eosinophilic esophagitis patients (63%, P < 0.001); heartburn was more common in noneosinophilic esophagitis patients (53%, P < 0.001). Endoscopic rings were more common in eosinophilic esophagitis patients (27%, P = 0.023); hiatus hernia was more common in noneosinophilic esophagitis patients (11%, P = 0.022). Eosinophils were more numerous in eosinophilic esophagitis biopsies (mean 39/hpf, P < or = 0.001). Only eosinophilic esophagitis biopsies had eosinophilic microabscesses (42%, P < or = 0.001). Edema, basal zone hyperplasia, lamina propria papillae elongation and lamina propria eosinophils were commoner in eosinophilic esophagitis (P < or = 0.001-0.002), while lamina propria fibrosis was specific for eosinophilic esophagitis (39%, P < 0.001). Eosinophilic esophagitis is a disease with a predilection for young males with dysphagia and rings on endoscopy. Biopsies in eosinophilic esophagitis have high epithelial eosinophil counts, averaging nearly 40/hpf. Increased awareness of eosinophilic esophagitis is necessary, since treatment with allergen elimination or anti-inflammatory therapy may be more effective than acid suppression.
BACKGROUND: Asthma is a chronic airway disease with inflammation characterized by physiological changes (airway hyper-responsiveness, AHR) and pathological changes (inflammatory cells infiltration and mucus production). Eosinophils play a key role in the allergic inflammation. But the causative relationship between eosinophils and airway inflammation is hard to prove. One of the reasons is lack of activation marker of murine eosinophils. We investigated the expression of CD69 on murine eosinophils in vitro, the relationship between the expression of CD69 on eosinophils from peripheral blood and bronchoalveolar lavage fluid and on airway inflammation in asthmatic mice. METHODS: Eosinophils from peripheral blood of IL-5 transgenic mice (NJ.1638) were purified. Mice were divided into five groups: wild type mice sensitized and challenged with saline (WS group), wild type mice sensitized and challenged with ovalbumin (WO group), IL-5(-/-) mice sensitized and challenged with saline and transferred with purified eosinophils (ISE group), IL-5(-/-) mice sensitized and challenged with OVA and transferred with purified eosinophils (IOE group), IL-5(-/-) mice sensitized and challenged with OVA and transferred with purified eosinophils, pretreated with anti CD4 monoclonal antibody (IOE+antiCD4mAb group). IL-5(-/-) mice were sensitized with OVA at day 0 and day 14, then challenged with OVA aerosol. On days 24, 25, 26 and 27 purified eosinophils were transferred intratracheally to IL-5(-/-) mice. On day 28, blood and BALF were collected and CD69 expression on eosinophils measured by flowcytometry. RESULTS: Purified eosinophils did not express CD69. But eosinophils cultured with PMA + MA, IFN-gamma, IL-5 or GM-CSF expressed CD69 strongly. Eosinophils from blood of WO, WS group did not express CD69 at all. The numbers of eosinophils in BALF of WO group, IOE group, ISE group and IOE + antiCD4mAb group were significantly higher than in mice of WS group which did not have eosinophils at all. CD69 expression on eosinophils in BALF of IOE and WO groups was strong. Eosinophils in BALF of ISE and IOE + antiCDmAb groups did not express CD69. The mucus production result was similar to CD69 expression. There were eosinophils infiltration in lung slides of all groups except WS group. CONCLUSION: Activation in airway of eosinophils could directly lead to airway inflammation.
Interleukin-5 (IL-5) transgenic mice were used to assess the immunological features of CSF eosinophils from mice infected with Angiostrongylus cantonensis. CSF eosinophils were hypodense by day 14 post infection (p.i.). CSF eosinophils survived longer in vitro than peritoneal eosinophils collected from cadmium sulphate (CdSO(4)) -treated normal IL-5 transgenic mice. Apoptosis was measured by Annexin V binding and the presence of a distinct laddering pattern of DNA fragmentation on agarose electrophoresis. Regardless of the presence or absence of Actinomycin D, CSF eosinophils collected from IL-5 transgenic mice from days 15-36 p.i. exhibited less apoptosis than peritoneal eosinophils collected from uninfected IL-5 transgenic mice. CSF eosinophils collected from A. cantonensis infected C57BL/6 mice at days 15-34 p.i. showed elongation of survival time and less apoptosis during in vitro cultivation. Reduced apoptosis was noted only in CSF eosinophils, but not in peritoneal eosinophils recovered from the same infected IL-5 transgenic mice. CPP32/Caspase 3 activity of cultured peritoneal eosinophils from both infected and uninfected IL-5 transgenic mice was higher than that of cultured CSF eosinophils. Stimulation with A23187 readily induced apoptosis of peritoneal eosinophils, but not CSF eosinophils or peritoneal eosinophils cultured with mouse recombinant IL-5. The latter cells were morphologically identical to hypodense eosinophils. RT-PCR analysis indicated that bcl-2 and bcl-x(L) mRNA expression was higher in CSF eosinophils compared with peritoneal eosinophils and this expression in the latter cells was upregulated after culture with mouse recombinant IL-5. These results suggest that CSF eosinophils, shifting to hypodense status through an accumulation from peripheral blood, are resistant to apoptosis. These changes may explain the long-lasting, helminthotoxic and neurotoxic actions of CSF eosinophils in A. cantonensis infection.
Therapeutic doses of corticosteroids frequently induce eosinopenia; however, the mechanism(s) involved remain obscure. To investigate this question, we studied the effects of corticosteroids on eosinophil adherence and migration. Eosinophils from normal donors were prepared by dextran sedimentation and Hypaque gradient centrifugation to 45-96% purity. Adherence was measured by filtration of whole blood and isolated eosinophils through nylon wool columns. Before prednisone administration, adherence was 83.8+/-3.2% for eosinophils in heparinized blood and 82.1+/-3.2% for isolated eosinophils. 4 h after oral prednisone administration whole blood eosinophil adherence was reduced to 53.9+/-10.7%; at 24 and 48 h adherence was normal. In contrast, isolated eosinophils showed no decrease in adherence 4, 24, or 48 h after corticosteroid administration. Similarly, in vitro addition of hydrocortisone to isolated eosinophils at 0.01 and 2.0 mg/ml did not reduce adherence. Eosinophil migration was tested in modified Boyden chambers by "lower-surface" and "leading-front" methods, using zymosan-activated serum and buffered saline to assess chemotactic and random migration, respectively. In vitro incubation of eosinophils with hydrocortisone or methylprednisolone produced a dose-dependent inhibition of chemotaxis. Using lower-surface methods the minimal concentration effecting substantial inhibition was 0.01 mg/ml for both drugs. At 2.0 mg/ml hydrocortisone and methylprednisolone inhibited eosinophil chemotaxis 82.6+/-4.4% and 85.0+/-3.5%, respectively. Using leading-front chemotaxis techniques significant inhibition was detected at 0.001 mg/ml hydrocortisone. Eosinophils incubated and washed free of corticosteroids responded normally to chemoattractants, indicating that the inhibitory effect of these drugs was reversible. Hydrocortisone at 2 mg/ml inhibited random eosinophil migration, although this effect was not apparent at lower concentrations. Corticosteroids did not act as chemotactic factor inactivators and were not toxic as measured by trypan blue exclusion. Eosinophils obtained from donors who had received 40 mg of prednisone orally for four days showed normal chemotactic responses, probably reflecting the fact that the cells were washed free of plasma before testing. In contrast, incubation of eosinophils in plasma from donors who had received a 300-mg bolus of hydrocortisone induced 46.1+/-4.5% more inhibition of chemotaxis than did incubation in normal plasma. These results indicate that: (a) eosinophil adherence is transiently reduced following in vivo corticosteroid administration, (b) eosinophil chemotaxis is inhibited by both in vitro and in vivo administration of corticosteroids, and (c) the chemotaxis inhibiting effect is nontoxic, cell-directed, dose-dependent and reversible. Inhibition of eosinophil adherence and chemotaxis may in part explain how corticosteroids produce eosinopenia and decrease the local accumulation of eosinophils.
The secretion of preformed granule proteins by eosinophils is an important correlate of eosinophil activation. However, a review of the literature reveals large disparities in the amounts of these substances which were reportedly secreted when eosinophils were activated. In the present study we report that our attempts to quantitate the secretion of eosinophil peroxidase and eosinophil-derived neurotoxin from activated eosinophils by measuring these substances in the incubation supernatants were uniformly unsuccessful. We found that, once they were secreted, both eosinophil peroxidase and eosinophil-derived neurotoxin were promptly lost to assay and presumably destroyed. Thus the measurement of the difference in the concentration of these substances in eosinophils prior to and after activation, revealed that as much as 65% of the eosinophil-derived neurotoxin and 62% of the peroxidase in the eosinophils were lost to assay during activation of the cells whereas the largest amount of these substances which could be measured in the incubation supernatants never exceeded 2%. Evidence is presented that the destruction of eosinophil-derived neurotoxin must occur prior to the release of this substance into the medium. Attempts to inhibit the destruction of eosinophil peroxidase and of eosinophil-derived neurotoxin by incorporating various inhibitors into the incubations were unsuccessful. These results emphasize the need to monitor the overall recoveries of secreted products from activated eosinophils and suggest that meaningful estimates of the secretion of these granule proteins from activated eosinophils can only be obtained by measuring the residual content of these substances in eosinophils after they have been activated and comparing these values to the contents of eosinophils prior to activation.
BACKGROUND: Eosinophilic inflammation of the airways is a key characteristic of asthma. A defect in apoptosis might contribute to the chronic tissue eosinophilia associated with asthma. OBJECTIVE: Our purpose was to examine whether the rate of apoptosis differs between peripheral blood eosinophils from asthmatic patients and healthy volunteers. METHODS: Peripheral blood was obtained from volunteers with asthma and from control volunteers. Eosinophils were isolated by CD16-negative selection to >99% purity and were cultured for 48 hours. The number of apoptotic eosinophils in the culture was assessed by flow cytometric analysis of relative DNA content in propidium iodide-stained cells. Eosinophil apoptosis is expressed as apoptosis index (number of apoptotic cells/total number of cells). RESULTS: Eosinophils from asthmatic patients not taking steroid medication survived longer (apoptosis index 0.25) than those of healthy control subjects (apoptosis index 0.40, P <.05). In contrast, the rate of apoptosis in eosinophils from patients concurrently taking steroids (apoptosis index 0.46) is higher than that of those not using steroids (P <.01) and not different from that of healthy subjects. To assess whether endogenous IL-3, IL-5, and GM-CSF production contributes to the delayed eosinophil apoptosis, the effects of the corresponding neutralizing antibodies were studied on eosinophil longevity. Neutralization of GM-CSF, but not of IL-3 or IL-5, increased slightly but significantly (P <.01) the rate of apoptosis in eosinophils obtained from patients with asthma. To assess whether beta(2)-agonist medication could contribute to the observed differences, we determined the in vitro effects of albuterol, fenoterol, and salmeterol on eosinophil apoptosis. All beta(2)-agonists inhibited eosinophil apoptosis by 12% to 19%. A possibility existed that a prior in vivo exposure to IL-5, GM-CSF, or beta(2)-agonists would explain the observed difference. To study this, eosinophils were incubated with GM-CSF, IL-5, and albuterol for 2 to 3 hours, followed by washout of the added compounds, and were subsequently cultured for 48 hours. However, an exposure to GM-CSF (7 pmol/L) or IL-5 (10 pmol/L) for 15 to 180 minutes was not a sufficient signal to prevent eosinophil apoptosis. In contrast, exposure to albuterol (100 nmol/L) for 120 minutes was sufficient to induce a significant (P <.05) decrease in eosinophil apoptosis. CONCLUSIONS: The results suggest that eosinophil apoptosis is delayed in asthma. This delay may be partly explained by production of GM-CSF. The in vitro effects of beta(2)-agonists suggest that beta(2)-agonist use might contribute to the prolonged eosinophil survival through inhibition of apoptosis and thus may worsen eosinophilia in asthmatic patients. Use of inhaled glucocorticoids seems to totally reverse the delayed eosinophil apoptosis in asthma.
BACKGROUND: "Vacuolated" eosinophils (ie, eosinophils with empty, nonstaining granules) have been described previously in normal Greyhounds. However, to our knowledge, detailed studies of granules in vacuolated and normal eosinophils in this breed have not been performed. OBJECTIVE: The objective of this prospective study was to characterize some of the morphologic, ultrastructural, and cytochemical staining features of specific (primary) granules in both normal and vacuolated eosinophils in Greyhound blood. METHODS: Morphologic features of eosinophils in Wright's- and Diff-Quik-stained peripheral blood smears from 49 Greyhounds were compared with 200 blood smears from non-Greyhound dogs. Transmission electron microscopy was done on blood from 3 Greyhounds with vacuolated eosinophils and 3 with normal eosinophil granules. Blood smears from 4 of these dogs also were stained cytochemically with alkaline phosphatase (AP), chloracetate esterase (CAE), and alpha naphthyl butyrate esterase (ANBE). The morphologic features and tinctorial properties of vacuolated and normal eosinophils were compared. RESULTS: Twenty-six Greyhounds (53%) had vacuolated eosinophils and 23 (47%) had normal granulated eosinophils in smears stained with Wright's stain. Only 1% of eosinophils were vacuolated in non-Greyhound dogs. Twenty of the 23 (85%) Greyhounds with normal granulated eosinophils on Wright's-stained smears had vacuolated eosinophils in smears stained with Diff-Quik. Ultrastructurally, no morphologic differences were observed between granules of vacuolated and normal eosinophils. Both vacuolated and normal eosinophils in Greyhounds were positive for AP and negative for CAE and ANBE, as expected for normal dogs. CONCLUSION: Vacuolated eosinophils in Greyhounds likely reflect, at least in part, differential staining properties of the specific granules with different hematologic stains. Ultrastuctural and cytochemical features of eosinophil granules were similar in normal and vacuolated eosinophils from Greyhounds.
BACKGROUND: Eosinophils play important roles in tissue inflammatory responses associated with helminth infections. Excretory-secretory products (ESP) produced by tissue-invasive helminths contain a large quantity of proteolytic enzymes that can modulate the host's immune responses. However, little is known regarding the roles of worm-derived products that are responsible for eosinophilic inflammatory responses in helminth infections. OBJECTIVE: In the present study, we investigated whether ESP produced by Paragonimus westermani, which cause pulmonary or extrapulmonary paragonimiasis in human beings, regulates both cell survival and death of human eosinophils. METHODS: The ESP was obtained from P. westermani newly excysted metacercariae (PwNEM). Eosinophils were purified from peripheral blood of healthy donors, and the purified eosinophils were incubated with or without the ESP secreted by PwNEM. The viability of eosinophils was assessed by staining with propidium iodide using the flow cytometer. RESULTS: When eosinophils were incubated with a low concentration of the ESP produced by PwNEM, which totally consists of proteolytic enzymes, eosinophil cell death was delayed compared with results for cells incubated with medium alone. In fact, the ESP at a low concentration stimulated eosinophils to produce detectable levels of GM-CSF that can delay eosinophil cell death. In contrast, eosinophil cell death was dose-dependently accelerated when cells were incubated with high concentrations of the ESP. To see whether the dose-dependent biphasic survival effect of the ESP on eosinophils is primarily due to the protease activity contained in the ESP, a high dose of the ESP was treated with heat at 56 degrees C for 30 min before being added to eosinophils. Attenuating protease activity in a high dose of the ESP by heat treatment reversed the ESP-afforded eosinophil cell death. This prolonged survival of eosinophils induced by the heated ESP was remarkably inhibited by anti-GM-CSF-neutralizing mAb and Jak2 kinase inhibitor AG-490. CONCLUSION: These results suggest that the proteases in the ESP secreted by PwNEM are able to regulate eosinophil survival through the autocrine production of GM-CSF. Thus, the enhanced eosinophil survival induced by Paragonimus-secreted products may contribute to the elicitation of eosinophilic inflammatory responses at the worm-infected lesion in human paragonimiasis.