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PubMed2000

Eosinophilic apoptosis in sinus mucosa: relationship to tissue eosinophilia and its resolution in allergic sinusitis.

BACKGROUND: Apoptosis, which is regulated by both cell survival and death signals, is important for the swift clearance of unwanted cells. OBJECTIVE: We sought to elucidate whether eosinophilic apoptosis is associated with tissue eosinophilia and to determine its resolution in allergic sinusitis (AS). METHODS: Numbers of eosinophils, numbers of IL-5(+) cells, and the apoptosis index of eosinophils were calculated in the submucosa (both superficial and deep layers) of patients with AS by using histochemical methods before and after prednisolone treatment. Patients without AS were used for control groups. Anti-EG2 antibody was used to identify eosinophils. IL-5, Fas, or Bax expression of eosinophils was evaluated to elucidate the role of the factors affecting eosinophilic apoptosis. RESULTS: EG2 and IL-5(+) cells were abundant in the submucosa of patients with AS, especially in the superficial layer. About 50% to 60% of the IL-5-producing cells were eosinophils. Apoptotic eosinophils were less numerous in the superficial layer than the deep layer in these diseases. After prednisolone treatment, an induction of eosinophilic apoptosis was accompanied by a significant decrease in the number of EG2(+) and IL-5(+) cells. No remarkable difference was observed in the Fas or Bax expression of eosinophils after prednisolone treatment. CONCLUSION: Autocrine secretion of IL-5 from eosinophils may be one reason why eosinophilic disease is difficult to manage. Induction of eosinophilic apoptosis is critical for reversing tissue eosinophilia in patients with AS.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

Degranulation patterns of eosinophils in advanced gastric carcinoma: an electron microscopic study.

Recruitment and activation of eosinophils have been studied intensely in asthma and other allergic diseases. Less is known about the infiltration and degranulation patterns of eosinophils in the tumor stroma. Seven cases of advanced gastric carcinomas were found to be massively infiltrated by eosinophils and studied by light and electron microscopy. Gastric carcinomas, despite having similar numbers of tissue eosinophils, exhibited markedly different degranulation patterns. In 2 cases, resting nondegranulating eosinophils were found. Piecemeal degranulation was the predominant mode of secretion from eosinophils localized within the tumor stroma in 4 cases. Eosinophil exocytosis and cytolysis were rarely observed. In 1 case, crystals morphologically similar to Charcot-Leyden crystals were observed at the extracellular level as well as in phagosomes of tissue macrophages, confirming active sequestrations of eosinophil Charcot-Leyden protein by macrophages in vivo. In the same case, eosinophils showed characteristic features of early and late apoptotic changes, such as condensed chromatin, focal dilatation of nuclear envelope, and preserved plasma membrane. Morphological association between apoptotic eosinophils and deposition of granules in the tumor stroma was found. Extracellular deposition of intact granules from apoptotic eosinophils was distinct from eosinophilic (necrotic) cytolysis, and has reported previously in experimental studies in vitro. To the knowledge of the authors, this case represents the first report of late apoptotic eosinophils that release their granules within the tumor stroma in a human gastric carcinoma.

Aged↗

PubMed1990

Human eosinophils express transforming growth factor alpha.

Transforming growth factor alpha (TGF-alpha) is a pleuripotential cytokine with diverse biological effects, including the ability to influence the proliferation of normal cells or neoplastic epithelial cells. Eosinophils are a subset of granulocytes that normally enter the peripheral tissues, particularly those beneath gastrointestinal, respiratory, and urogenital epithelium, where they reside in close proximity to the epithelial elements. In this study, we demonstrate that the great majority of eosinophils infiltrating the interstitial tissues adjacent to two colonic adenocarcinomas and two oral squamous cell carcinomas labeled specifically by in situ hybridization with a 35S-riboprobe for human TGF-alpha (hTGF-alpha). No other identifiable leukocytes in these lesions contained detectable hTGF-alpha mRNA. We also examined leukocytes purified from a patient with the idiopathic hypereosinophilic syndrome. 80% of these eosinophils, but none of the patient's neutrophils or mononuclear cells, were positive for hTGF-alpha mRNA by in situ hybridization, and 55% of these eosinophils were positive by immunohistochemistry with a monoclonal antibody directed against the COOH terminus of the mature hTGF-alpha peptide. Finally, the identification of the purified eosinophil-associated transcript as hTGF-alpha was confirmed by polymerase chain reaction product restriction enzyme analysis followed by Southern blot hybridization. In contrast to eosinophils from the patient with hypereosinophilic syndrome, the peripheral blood eosinophils from only two of seven normal donors had detectable TGF-alpha mRNA and none of these eosinophils contained immunohistochemically detectable TGF-alpha product. Taken together, these findings establish that human eosinophils can express TGF-alpha, but suggest that the expression of TGF-alpha by eosinophils may be under microenvironmental regulation. Demonstration of TGF-alpha production by tissue-infiltrating eosinophils and the eosinophils in the hypereosinophilic syndrome identifies a novel mechanism by which eosinophils might contribute to physiological, immunological, and pathological responses.

Adenocarcinoma↗

PubMedDate not supplied

Tissue eosinophilic infiltration: a useful marker for assessing stromal invasion, survival and locoregional recurrence in head and neck squamous neoplasia.

UNLABELLED: The assessment of stromal invasion in aerodigestive neoplastic squamous proliferation often poses diagnostic and therapeutic challenges. Eosinophilic infiltration is thought to be an adjunctive histologic criterion in determining tumor aggressiveness and invasion. We investigated whether an eosinophilic infiltration in head and neck squamous cell carcinoma measured in biopsies would aid in predicting tumor invasion, response to treatment, locoregional recurrence, and survival. METHODS: Eighty-seven patients with in situ and invasive squamous cell carcinoma of the head and neck region were evaluated and treated according to their staging. The number of eosinophils per high-power field (eosinophil/HPF), and per 10 high-power fields (eosinophil/10 HPF) at the tumor interface and in tumor tissue, was counted and classified as focally or diffusely present. Each sample was assigned an eosinophilic index of 1-4 based on the number of eosinophils/HPF or 10 HPF. Of 87 patients, 20 patients were followed up after appropriate treatment for locoregional recurrence, distant metastasis, and disease-free survival. RESULTS: Eosinophilic counts were elevated focally and/or diffusely more frequently in invasive squamous cell carcinoma than in noninvasive tumors. The increased eosinophilic counts, specifically > 10/HPF and > 20/10 HPF, were both significantly associated with stromal invasion. Greater than 10 eosinophils/HPF and/or > 20 eosinophils/10 HPF had the highest predictive power for invasion, with sensitivity, specificity, and positive predictive values of 66%, 94%, 96% and 61%, 100%, and 100%, respectively. Eosinophilic counts greater than 20 eosinophils/10 HPF and eosinophilic indices > 2 were virtually diagnostic for tumor invasion. Patients' biopsies with eosinophilic indices < 2 had a better survival (P = 0.0156). Using Cox regression analysis, we found that most patients' biopsies that had eosinophilic indices > 2 recurred locally or regionally. CONCLUSIONS: The elevated eosinophilic counts in biopsies and eosinophilic indices in specimens of squamous cell carcinoma of the aerodigestive tract are a histopathologic marker associated with tumor invasion and a clinical predictor for aggressive tumor biology. Similarly, the presence of eosinophils meeting these thresholds in an excisional specimen should indicate the need for additional therapeutic measures and close surveillance to detect earlier locoregional recurrence and possible distant metastasis.

Adult↗

PubMed1993

Interleukin-8 is a chemo-attractant for eosinophils purified from subjects with a blood eosinophilia but not from normal healthy subjects.

Interleukin-8 (IL-8), a pro-inflammatory cytokine with potent neutrophil chemotactic activity, was studied for its effect on eosinophil migration responses, in vitro. Normal density eosinophils were isolated from healthy, non-atopic subjects (<0.35 x 10(9) eosinophils/l) and individuals with various diseases associated with a blood eosinophilia (range 0.56 x 10(9)-12.2 x 10(9) eosinophils/l). IL-8 produced a dose-dependent migrational response for eosinophils from subjects with an eosinophilia, optimal at 10(-8) M (P < 0.01) and the major component of the migrational response was chemokinesis. On a molar basis, IL-8 (EC50 approximately 10(10) M) was 100-fold more potent than platelet activating factor (PAF), although a comparison of the migrational responses showed that at optimal concentrations IL-8 (10(-8) M) produced only 30% maximal responses stimulated by PAF (10(-6) M). In contrast, IL-8 tested over a wide concentration range had a negligible effect on eosinophils from normal subjects. A direct correlation between the total blood eosinophil counts for all subjects and the absolute magnitude of the migrational response to IL-8 (r = 0.727, P < 0.01 at 10(-8) M), PAF (r = 0.551, P < 0.03 at 10(-6) M) and N-formyl-methionyl-leucyl-phenylalanine (fMLP) (r = 0.689, P < 0.02 at 10(-8) M), suggested that heightened eosinophil migrational responses to inflammatory mediators may arise as a consequence of in vivo priming mechanism(s) associated with the development of an eosinophilia. In this regard, eosinophils derived from human cord blood mononuclear cells cultured in the presence of eosinophilopoietic cytokines IL-3 and IL-5, produced migrational responses to IL-8 and PAF, that were comparable with that of eosinophils from eosinophilic subjects. Furthermore, incubation of eosinophils from normal donors with IL-5 (optimal concentration 10(-9) M), significantly enhanced the subsequent migrational responses to both IL-8 (10(-8) M, P < 0.01) and PAF (10(-8) M, P < 0.05). Therefore, the increased responsiveness of eosinophils from eosinophilic subjects may reflect in vivo priming by IL-5 and this phenomenon may contribute partly to the mechanism(s) by which eosinophils preferentially accumulate at sites of allergic inflammation.

Cells, Cultured↗

PubMed2000

Eosinophil-adhesion-inducing activity produced by antigen-stimulated mononuclear cells involves GM-CSF.

BACKGROUND: The initial step of eosinophil accumulation in allergic inflammation is adhesion of circulating eosinophils to vascular endothelial cells (EC). There is evidence that the adhesive property of circulating eosinophils is upregulated following antigen exposure. Although the exact mechanism remains to be established, cytokine(s) produced by antigen-stimulated mononuclear cells is (are) likely key factor(s). OBJECTIVE: The objective of this study was to examine the factor(s) responsible for eosinophil adhesion and migration induced by the antigen-stimulated mononuclear cells obtained from atopic asthmatics. METHODS: Peripheral blood mononuclear cells (PBMC) isolated from house-dust-mite-sensitive bronchial asthmatics were cultured for 96 h in the presence or absence of 1 microg/ml Dermatophagoides farinae (Df) antigen. Eosinophils were isolated from peripheral blood of healthy subjects. Eosinophil-adhesion-inducing activity in the culture supernatants of PBMC was examined by the ability to modify the adhesion of eosinophils to human pulmonary microvascular endothelial cells (HPMEC) in the presence or absence of anti-cytokine/chemokine antibodies. Eosinophil migration induced by the supernatants was also examined. RESULTS: Eosinophil adhesion to HPMEC was significantly augmented by the supernatants of Df-stimulated PBMC, which was significantly inhibited by anti-GM-CSF, but not by anti-IL-5, anti-RANTES, or isotype-matched controls. On the other hand, eosinophil migration induced by the supernatants was inhibited by anti-GM-CSF and partly by anti-RANTES. CONCLUSION: Both eosinophil adhesion and migration induced by the antigen-stimulated PBMC involve GM-CSF. In contrast, RANTES is involved only in the eosinophil migration. These molecules may participate in the development of eosinophil accumulation at the allergic inflammation sites.

Antigens↗

PubMed2004

Caspase-3-mediated apoptosis of human eosinophils by the tissue-invading helminth Paragonimus westermani.

BACKGROUND: Eosinophils are important cells in host immunity to infections by parasitic worms. Tissue-invasive helminthic parasites have been known to induce apoptosis of immune cells for their successful establishment in vivo. We have previously found that high doses of excretory-secreted products (ESP) secreted by lung fluke Paragonimus westermani newly excysted metacercariae (PwNEM), which cause pulmonary or extrapulmonary paragonimiasis in human beings, accelerate eosinophil cell death. However, little is known about the mechanism of eosinophil apoptosis induced by the Paragonimus-derived products. OBJECTIVE: We examined involvement of caspase 3 activation in eosinophil cell death induced by ESP produced by PwNEM. METHODS: Eosinophils were isolated from the peripheral blood of healthy donors by CD16-negative immunomagnetic selection. We examined the inhibitory effect of pan-caspase inhibitor on ESP-triggered phosphatidylserine (PS) externalization on the outer surface of eosinophils and intracellular activation of caspase 3 in cell lysates treated with the ESP. RESULTS: When ESP secreted by PwNEM were incubated for up to 3 h with eosinophils, they increased surface exposure of PS on eosinophils in a time- and dose-dependent manner. This proapoptotic effect of the ESP on eosinophils was significantly inhibited by pretreatment of cells with pan-caspase inhibitor z-VAD-fmk, and was completely abolished by heat inactivation of ESP at 56 degrees C. The activated forms of caspase 3 were also clearly detected in eosinophils incubated with ESP. Moreover, ESP potently inhibited prolonged survival of eosinophils induced by cytokines such as IL-5, IL-3, and GM-CSF. CONCLUSION: These results suggest that ESP secreted by PwNEM contain biological active factors causing caspase-3-mediated apoptosis of human eosinophils, thereby enabling the larvae to evade and to subvert the tackle by eosinophils during the early phase of the infection.

Amino Acid Chloromethyl Ketones↗

PubMedDate not supplied

Differentiation of eosinophils from cord blood cell precursors: kinetics of Fc epsilon RI and Fc epsilon RII expression.

Expression of Fc epsilonRI and Fc epsilonRII/CD23 was examined by immunocytochemistry and flow cytometry on eosinophils differentiated from human cord blood cells in the presence of human interleukin-3 (rhIL-3), granulocyte/macrophage colony stimulating factor (rhGM-CSF) and interleukin-5 (rhIL-5) and on blood eosinophils purified from normal donors or patients with idiopathic hypereosinophilic syndrome (HES). On cord blood derived eosinophils, Fc epsilonRI expression started at 1 week of culture and increased to reach a plateau at 3 weeks of culture. Fc epsilonRII/CD23 appeared slightly later, after 2 weeks of culture, and the percentage of Fc epsilonRII/CD23-positive eosinophilic cells increased and stayed in plateau. Fc epsilonRI expression on cord blood derived eosinophils was downregulated after culture with interleukin-2 (rhIL-2), interleukin-4 (rhIL-4), rhIL-5, interferon-alpha (rhIFN-alpha), interferon-gamma (rhIFN-gamma). In contrast, the expression of Fc epsilonRII/CD23 on cord blood derived eosinophilic cells was upregulated after culture with rhIL-4, rhIL-5 and rhIFN-gamma, and downregulated with rhIL-2 and rhIFN-alpha. Fc epsilonRI was expressed on about 30% normal donor eosinophils as well as on normodense eosinophils from HES patients but significantly decreased on hypodense eosinophils. In contrast, Fc epsilonRII/CD23, expressed on a very small proportion of normal donor eosinophils, increased from normodense to hypodense eosinophils. These results suggest that Fc epsilonRI on eosinophils might represent one differentiation antigen expressed relatively early, with decreased expression through maturation or activation, whereas Fc epsilonRII/CD23 might rather be considered as a marker of eosinophil activation.

Cell Differentiation↗

PubMed1996

Eosinophil apoptosis and the resolution of airway inflammation in asthma.

Asthma is accompanied by the accumulation of potentially damaging eosinophils within inflamed airways. How eosinophils may be removed from the airways is not clear. The phagocytic removal of eosinophils in vitro requires that they undergo apoptosis, a form of cell death. We postulated that eosinophil apoptosis may occur in vivo, promoting the removal of airway eosinophils and the resolution of inflammation in asthma. We examined eosinophil apoptosis in sputum samples obtained from 11 subjects during an asthma exacerbation and 2 wk after corticosteroid treatment of the exacerbation. Airway function improved following corticosteroid treatment, and eosinophilic inflammation subsided, with significant decreases occurring in the number of airway eosinophils and the percentage of activated eosinophils. The proportion of apoptotic airway eosinophils increased significantly following corticosteroid treatment, and eosinophil products were apparent within macrophages. Our findings indicate that eosinophil apoptosis is clinically relevant in asthma. Apoptosis may represent a mechanism that promotes the resolution of eosinophilic inflammation in asthma.

Adrenal Cortex Hormones↗

PubMed2004

Occurrence of apoptosis, secondary necrosis, and cytolysis in eosinophilic nasal polyps.

The paradigm states that inflammatory cells disappear from airway tissues through apoptosis and phagocytosis. However, cells may also be cleared through primary cytolysis, necrosis secondary to apoptosis, or transepithelial migration. This study examines the occurrence of apoptosis, secondary necrosis, and cytolysis of eosinophils in human nasal polyps in vivo and blood eosinophils in vitro. Eosinophils abounded in subepithelium and in paracellular epithelial pathways. Macrophages commonly occurred but without engulfed eosinophils. Scattered cells, including epithelial cells, were stained by antibody to the caspase cleavage product of poly(ADP-ribose) polymerase. Few cells were apoptotic (stained by terminal deoxy RNase nick end labeling). Of more than 3,000 examined tissue eosinophils, 110 were caspase cleavage positive, but only one was apoptotic. Transmission electron microscopy analysis of more than 500 eosinophils revealed viable and cytolytic eosinophils but not apoptosis, secondary necrosis, or engulfment of eosinophils. Plasma cells but neither epithelial cells nor eosinophils exhibited apoptotic ultrastructural morphology. Eosinophils in vitro exhibited different stages of apoptosis, ending with secondary necrosis distinct from in vivo eosinophil cytolysis. Our results show that the clearance of eosinophils from nasal polyps largely occurs through nonapoptosis pathways, including cytolysis and paraepithelial migration, and they challenge the belief that apoptosis is important for clearance of eosinophils from respiratory tissues.

Apoptosis↗

PubMed2001

Degranulation status of airway tissue eosinophils in mouse models of allergic airway inflammation.

Eosinophil degranulation is a characteristic feature of asthma and allergic rhinitis. However, degranulated eosinophils have not been convincingly demonstrated in the common mouse models of these airway diseases. This study uses eosinophil peroxidase (EPO) histochemistry and transmission electron microscopy (TEM) analysis to assess eosinophil degranulation in the airways of ovalbumin (OVA)-sensitized and challenged BALB/c and C57BL/6 mice. Using TEM we also examined mouse and human blood eosinophils after in vitro incubation with formyl-Met-Leu-Phe (fMLP) or phorbol myristate acetate (PMA). Although OVA exposure induced significant nasal and lung eosinophilia, we did not observe any of the known cellular processes by which eosinophils release their granule products, i.e., eosinophil cytolysis, piecemeal degranulation, and exocytosis. The occurrence of other allergen-induced degranulation events was ruled out because no difference in granule morphology was observed between lung-tissue eosinophils and blood or bone-marrow eosinophils from control animals. Accordingly, there was no detectable extracellular EPO in lung tissues of allergic mice. Similarly, mouse blood eosinophils remained nondegranulated in vitro in the presence of fMLP and PMA, whereas the same treatment of human eosinophils resulted in extensive degranulation. This investigation indicates that OVA-induced airway inflammation in the present mouse strains does not involve significant eosinophil degranulation. It is speculated that this dissimilarity from the human disease may be due to a fundamental difference in the regulation of mouse and human eosinophils.

Animals↗

PubMed1991

Airway eosinophils from actively sensitized guinea pigs exhibit enhanced superoxide anion release in response to antigen challenge.

Antigen challenge of actively sensitized guinea pigs produces airway eosinophilia, airway hyperreactivity, and late-phase bronchoconstriction. The recruited eosinophils are thought to be important cells in the development of the airway hyperreactivity and the late-phase bronchoconstriction. However, the functional abilities of these eosinophils have not been determined in response to antigen challenge. The purpose of this study was to describe the characteristics of superoxide anion release from airway eosinophils obtained 24 h after ovalbumin challenge of actively sensitized guinea pigs. Eosinophils were collected by bronchoalveolar lavage. The total bronchoalveolar lavage eosinophil count was 17- to 27-fold greater in sensitized, ovalbumin-challenged guinea pigs (9.30 +/- 0.11 x 10(6)/guinea pig) than in unsensitized guinea pigs (0.35 +/- 0.07 x 10(6)/guinea pig) or sensitized, saline-challenged guinea pigs (0.56 x 10(6)/guinea pig; n = 2). The increase in eosinophils was due to increased lavage leukocyte count and increased eosinophil differential. Eosinophils were isolated on a Percoll-plasma discontinuous gradient. Two populations of eosinophils were collected, one at the 1.093 g/ml gradient step and one at the 1.107 g/ml gradient step. Unstimulated or phorbol myristate acetate (PMA)-stimulated superoxide anion release was measured by the reduction of ferricytochrome c. Unstimulated superoxide anion release from both eosinophil populations of challenged guinea pigs (4.50 +/- 2.37 and 4.07 +/- 1.48 nmol from 1.093 and 1.107 g/ml eosinophils, respectively) was 6- to 7-fold greater than superoxide anion release from eosinophils of control guinea pigs (0.74 +/- 0.43 and 0.56 +/- 025 nmol from 1.093 and 1.107 g/ml eosinophils, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Selective eosinophil leukocyte recruitment by transendothelial migration and not by leukocyte-endothelial cell adhesion.

Eosinophil infiltration is the hallmark of allergic inflammatory events. However, the mechanisms governing the influx of eosinophils into the tissue at a site of an allergic reaction remains unclear. We have examined the interactions of eosinophils and neutrophils isolated from the same atopic donor with cultured human umbilical vein endothelial cell (EC) monolayers in the search for a mechanism for this selective eosinophil recruitment. First, the adherence of eosinophils and neutrophils to ECs stimulated with lipopolysaccharide, interleukin (IL)-1 alpha, and tumor necrosis factor-alpha were compared. Each mediator induced a similar dose-dependent enhancement of eosinophil adhesiveness for both eosinophils and neutrophils. Thus, although cytokine activation of ECs in the vasculature adjacent to an inflammatory site probably serves as an important focusing mechanism for the extravasation of inflammatory cells at this site, there does not appear to be any selective EC-dependent mechanism for eosinophil recruitment. Little or no effect on eosinophil and neutrophil adherence was observed with IL-3, IL-5, granulocyte/macrophage colony-stimulating factor, platelet-activating factor (PAF), leukotriene B4, or histamine. Second, the migration of eosinophils and neutrophils through an EC monolayer in response to chemoattractants was examined. PAF was found to selectively enhance eosinophil transendothelial migration at doses of 10(-7) to 10(-10) M, with optimal effect at 10(-8) M. This effect was gradient dependent and could be inhibited by WEB 2086, a specific PAF inhibitor. These results suggest that localized production of PAF may be a prime factor in the events leading to eosinophil accumulation at allergic inflammatory sites, and that selectivity for eosinophil recruitment occurs at the stage of transendothelial cell migration under the influence of cell-specific chemoattractants.

Amitrole↗

PubMed1988

Human eosinophils have prolonged survival, enhanced functional properties, and become hypodense when exposed to human interleukin 3.

Human eosinophils were cultured in the presence of recombinant human IL-3 for up to 14 d and their biochemical, functional, and density properties were assessed. After 3 d of culture in 10 pM IL-3, eosinophils had a viability of 70% compared with only 10% in enriched medium alone. Neither IL-1 alpha, IL-2, IL-4, tumor necrosis factor, basic fibroblast growth factor, nor platelet-derived growth factor maintained eosinophil viability. The 7- and 14-d survival of the cultured eosinophils was 55 and 53%, respectively. No other cell type, including neutrophils, was present after culture. After 7 d of culture, the normodense eosinophils were converted to hypodense cells as assessed by density centrifugation. Eosinophils exposed to 1,000 pM IL-3 for 30 min or cultured in 10 pM IL-3 for 7 d generated approximately threefold more leukotriene C4 (LTC4) in response to calcium ionophore than freshly isolated cells. Furthermore, whereas freshly isolated eosinophils killed only 14% of the antibody-coated Schistosoma mansoni larvae, these eosinophils killed 54% of the larvae when exposed to 100 pM IL-3. The enhanced helminth cytotoxicity was maintained for 7 d when eosinophils were cultured in the presence of both 10 pM IL-3 and 3T3 fibroblasts, but not when eosinophils were cultured in the presence of IL-3 alone. IL-3 thus maintains the viability of eosinophils in vitro, augments the calcium ionophore-induced generation of LTC4, enhances cytotoxicity against antibody-sensitized helminths, and induces the eosinophils to become hypodense cells. These phenotypic changes in the eosinophil may be advantageous to host defense against helminthic infections but may be disadvantageous in conditions such as allergic disease.

Animals↗

PubMed1999

Fundamental signals that regulate eosinophil homing to the gastrointestinal tract.

The histological identification of increased eosinophils in the gastrointestinal tract occurs in numerous clinical disorders; however, there is a limited understanding of the mechanisms regulating eosinophil trafficking into this mucosal surface. The results presented in this study characterize the processes regulating eosinophil homing into the gastrointestinal tract at baseline. Eosinophils were found to be present in the lamina propria of 19-day-old embryos and germ-free adult mice at concentrations comparable to those present in non-germ-free adult mice. Furthermore, eosinophil gastrointestinal levels were not altered by increasing circulating eosinophils after pulmonary allergen challenge. Gastrointestinal eosinophil levels were partially reduced in mice deficient in recombinase activating gene-1 (RAG-1), IL-5, or the beta common chain (betac), but these reductions paralleled reductions in circulating eosinophils. In contrast, mice deficient in eotaxin had a marked reduction in gastrointestinal eosinophils but normal levels of eosinophils in the hematopoietic compartments. Furthermore, eotaxin was important for regulating eosinophil levels, even in the presence of high levels of IL-5. These investigations demonstrate eosinophil homing into the gastrointestinal tract during embryonic development occurring independently of viable intestinal flora. Furthermore, eotaxin is identified as the primary regulator of eosinophil gastrointestinal homing under homeostatic states, and may therefore have a fundamental role in innate immune responses.

Allergens↗

PubMed2005

Anti-Fas mAb-induced apoptosis and cytolysis of airway tissue eosinophils aggravates rather than resolves established inflammation.

BACKGROUND: Fas receptor-mediated eosinophil apoptosis is currently forwarded as a mechanism resolving asthma-like inflammation. This view is based on observations in vitro and in airway lumen with unknown translatability to airway tissues in vivo. In fact, apoptotic eosinophils have not been detected in human diseased airway tissues whereas cytolytic eosinophils abound and constitute a major mode of degranulation of these cells. Also, Fas receptor stimulation may bypass the apoptotic pathway and directly evoke cytolysis of non-apoptotic cells. We thus hypothesized that effects of anti-Fas mAb in vivo may include both apoptosis and cytolysis of eosinophils and, hence, that established eosinophilic inflammation may not resolve by this treatment. METHODS: Weeklong daily allergen challenges of sensitized mice were followed by airway administration of anti-Fas mAb. BAL was performed and airway-pulmonary tissues were examined using light and electron microscopy. Lung tissue analysis for CC-chemokines, apoptosis, mucus production and plasma exudation (fibrinogen) were performed. RESULTS: Anti-Fas mAb evoked apoptosis of 28% and cytolysis of 4% of eosinophils present in allergen-challenged airway tissues. Furthermore, a majority of the apoptotic eosinophils remained unengulfed and eventually exhibited secondary necrosis. A striking histopathology far beyond the allergic inflammation developed and included degranulated eosinophils, neutrophilia, epithelial derangement, plasma exudation, mucus-plasma plugs, and inducement of 6 CC-chemokines. In animals without eosinophilia anti-Fas evoked no inflammatory response. CONCLUSION: An efficient inducer of eosinophil apoptosis in airway tissues in vivo, anti-Fas mAb evoked unprecedented asthma-like inflammation in mouse allergic airways. This outcome may partly reflect the ability of anti-Fas to evoke direct cytolysis of non-apoptotic eosinophils in airway tissues. Additionally, since most apoptotic tissue eosinophils progressed into the pro-inflammatory cellular fate of secondary necrosis this may also explain the aggravated inflammation. Our data indicate that Fas receptor mediated eosinophil apoptosis in airway tissues in vivo may cause severe disease exacerbation due to direct cytolysis and secondary necrosis of eosinophils.

Animals↗

PubMed1992

Dual function of eosinophils in pathogenesis and protective immunity against parasites.

The functional duality of eosinophils, involved in a protective response or in pathogenesis is illustrated in various parasitic infections. In schistosomiasis, eosinophils have been shown to mediate schistosomula killing, in the presence of antibodies. The association of eosinophil-dependent cytotoxic antibody isotypes with resistance of reinfection (IgE and IgA antibodies), whereas in vitro blocking antibody isotypes (IgG4, IgM) were detected in susceptible subjects, suggested a participation of eosinophils in antibody-dependent protective response. However eosinophils could participate to granuloma formation and consequently to the pathological reactions during schistosomiasis. Activation of eosinophils by antibodies, leading to release of granule proteins have been studied in patients with filariasis. Eosinophil peroxidase, EPO was released after IgE-dependent activation whereas Eosinophil Cationic Protein, ECP, was released after IgG- and IgA-dependent activation of eosinophils, results suggesting a process of differential release of mediators. Interactions between eosinophils and interleukins, and specially IL-5 are discussed. Whereas a receptor for IL-5 has been characterized on human eosinophils, recent studies have shown that eosinophils expressed the messenger RNA encoding IL-5. These results associated to data showing the synthesis of other cytokines indicate that eosinophils are not only the source of cytotoxic mediators involved in the effector phase of immunity but also of growth and regulatory factors, participating to immunoregulation.

Animals↗

PubMed2000

The differential role of extracellular signal-regulated kinases and p38 mitogen-activated protein kinase in eosinophil functions.

The activation of eosinophils by cytokines is a major event in the pathogenesis of allergic diseases. We have investigated the activation of mitogen-activated protein (MAP) kinases and their functional relevance in eosinophil differentiation, survival, degranulation, and cytokine production. IL-5 induced phosphorylation and activation of extracellular signal-regulated kinases (ERK) and p38 MAP kinases in eosinophils. PD98059, a MAP/ERK kinase inhibitor, blocked phosphorylation of ERK1/2 in a dose-dependent manner. SB202190, a p38 inhibitor, blocked p38-dependent phosphorylation of activating transcription factor-2. To study the importance of the MAP kinases on eosinophil differentiation, we cultured mouse bone marrow cells with IL-3 and IL-5 in the presence of the inhibitors. SB202190 dramatically inhibited eosinophil differentiation by 71%. PD98059 was less potent and reduced eosinophil differentiation by 28%. Both inhibitors marginally inhibited eosinophil survival only at the highest doses. Prolonged incubation of eosinophils with IL-5 induced significant eosinophil-derived neurotoxin release. Both PD98059 and SB202190 nearly completely inhibited (87% and 100% inhibition, respectively) IL-5-stimulated eosinophil-derived neurotoxin release in a dose-dependent manner. Next, we examined the effect of the MAP kinase inhibitors on eosinophil production of the cytokine macrophage-inflammatory protein (MIP)-1alpha. PD98059 blocked C5a- but not ionomycin-induced MIP-1alpha production (59% inhibition at 50 microM concentration). In contrast, SB202190 nearly completely inhibited (99%) C5a-induced MIP-1alpha production. Further, it blocked ionomycin-stimulated production by 66%. Our results suggest that both p38 and ERK1/2 MAP kinases play an important role in eosinophil differentiation, cytokine production, and degranulation. The p38 MAP kinase plays a greater role than ERK1/2 in eosinophil differentiation and cytokine production.

Animals↗