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Byline: Karim Maghni (1), Francois Nantel (2), Chantal Lanoue (1), Solange Cloutier (1), Jean-Paul Cristol (1), Alain Cadieux (1), Pierre Sirois (1,2) Keywords: airway inflammation; hyperresponsiveness; eosinophil; guinea-pig Abstract: The effects of an intravenous injection of Sephadex beads on lung eosinophil infiltration and eosinophil peroxydase activity and its relationship to bronchial hyperresponsiveness was examined in guinea pigs. This Sephadex beads injection led to blood, lung and airway eosinophilia in association with bronchial hyperresponsiveness. Histologic examination of the lower bronchus indicated that the eosinophil number increased markedly in the mucosa and submucosa. In addition, the eosinophils surrounding the bronchioles 1 day after the Sephadex injection migrated further in airway submucosa and mucosa 7 and 14 days after. Moreover, the bronchial hyperresponsiveness is observed without histologic evidence of airway epithelium damage. Therefore, the bronchial hyperresponsiveness seems to be more related to the eosinophil infiltration in the airway epithelium and possibly eosinophil activation rather than to the eosinophil number recovered in the BAL fluid. We conclude that the maintenance of hyperresponsiveness state could be associated with the persistence of blood and airway eosinophilia. Author Affiliation: (1) Institute of Pharmacology of Sherbrooke, Medical School, University of Sherbrooke, Sherbrooke, P.Q., Canada, J1H 5N4 (2) IPS Pharma, 3001 North 12th Avenue, Sherbrooke, P.Q., Canada, J1H 5N4 Article History: Registration Date: 20/12/2004

Byline: N. Saito (), Y. Yamada (), S. Sannohe (), K. Honda (), T. Adachi (), H. Kayaba (), J. Chihara () Abstract: Adhesion molecules and C-C chemokines play an important role in the accumulation of eosinophils in allergic inflammation. In the present study, the expression and function of adhesion molecules on eosinophils from asthmatic patients and involvement of RANTES and eotaxin were examined. Eosinophils isolated by the CD16 negative selection method were stimulated with or without RANTES or eotaxin. Expression of b integrins on eosinophils and the functional adherence to recombinant soluble intercellular adhesion molecule-1 (r-sICAM-1)-coated plates were examined. Compared with normal subjects, eosinophils from asthmatic patients showed increased expression of b2 integrins and functional adherence to r-sICAM-1-coated plates. RANTES and eotaxin augmented the functional adherence of eosinophils without a significant upregulation of b2 integrins. Anti-b2 integrin antibody inhibited the augmentative effect on eosinophil adherence of RANTES and eotaxin. Pertussis toxin, wortmannin, and genistein inhibited chemokine-induced adherence. RANTES and eotaxin are closely related to eosinophil accumulation not only as chemotactic agents but also as augmentative agents for eosinophil adherence through involvement in functional eosinophil adherence to ICAM-1 by a possible qualitative change of b2 integrins. Pertussis toxin-sensitive G proteins, PI3 kinase, and tyrosine kinase are involved in signal transduction leading to activation of b2 integrins on eosinophil following stimulation with RANTES and eotaxin. Author Affiliation: () Department of Clinical and Laboratory Medicine, Akita University School of Medicine, 1-1-1 Hondo, Akita, Japan 010-8543, JP Article History: Accepted Date: 13/08/2002

Byline: Elizabeth Kudlacz (1), Carrie Whitney (1), Catharine Andresen (1), Maryrose Conklyn (1) Keywords: Eosinophil; chemokine; lung; rodent; eotaxin; adhesion molecules Abstract: Synergistic interactions between cytokines, chemokines and adhesion molecules may facilitate the selective recruitment of eosinophils into sites of allergic inflammation. Ovalbumin-sensitized IL5TG mice responded to antigen challenge with robust airway eosinophilia 24 and 72 hr post-exposure. Adhesion molecule expression and functional responsiveness of immune cells derived from IL5TG mice to various inflammatory mediators were evaluated. IL5TG-derived eosinophils, but not neutrophils, expressed higher levels of CD49d and CD11b relative to WT. Functional responsiveness to eotaxin was increased in IL5TG eosinophils as demonstrated by a 10x increase in its potency in producing actin polymerization and 3x increase in CD11b upregulation relative to WT. These data are consistent with increased CCR3 expression on IL5TG eosinophils. Responsiveness of eosinophils to LTB4 or MIP-1[alpha] was similar between WT and IL-5TG mice. These data provide evidence of synergy between eosinophil-specific cytokines and chemokines that may promote accumulation of this cell type under conditions of allergic inflammation in vivo. Author Affiliation: (1) Pfizer Global Research and Development, Eastern Point Road, Groton, CT, 06340 Article History: Registration Date: 12/10/2004

Byline: K. Fujimoto (), T. Tsunoda (), T. Koizumi (), K. Kubo () Abstract: Eosinophils have been shown to play a role in allergen-induced airway responses. The aim in this study was to examine the effects of TAK-661, a newly developed product as a specific inhibitory agent of eosinophil chemotaxis, on antigen-induced asthmatic responses in allergic sheep model. Seven Ascaris-sensitive, "dual-respondent" allergic sheep were provocated by an Ascaris suum antigen or phosphate-buffered saline 2 hrs after intra-stomach administration of TAK-661 or a placebo. Pulmonary resistances were measured throughout the experiment, and airway responsiveness to methacholine, bronchoalveolar lavage (BAL), and histological examination were performed 8 hrs after the antigen challenge. Antigen provocation induced dual-phase bronchoconstriction, eosinophilia in BAL and eosinophil infiltration into the airway wall, and an increase in airway responsiveness in placebo-treated sheep. The administration of TAK-661 significantly reduced the bronchoconstriction during the late phase, along with the inhibition of eosinophilia in BAL and the eosinophil infiltration into the airway wall. TAK-661 had a tendency to reduce early-phase bronchoconstriction and airway hyperresponsiveness, but there were no significant differences. These findings suggest that the eosinophil accumulation into the airway induced by antigen provocation may contribute to the development of late-phase bronchoconstriction, however, the development of airway hyperresponsiveness during late asthmatic response may not always be due to only eosinophilic inflammation in the airway. Author Affiliation: () The First Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390 Japan, JP Article History: Accepted Date: 23/04/2002

Byline: J. Gregory Noel (1), Denise A. Wells (1), Xialing Guo (1), Fansheng Kong (2), Glenda J. Lovell (1), Cora K. Ogle (1,2) Keywords: Thermal injury; myelopoiesis; eosinophils; GM-CSF; IL-5 Abstract: We have investigated the effects of thermal injury upon myelopoiesis. IL-3, GM-CSF, and IL-5 were used to stimulate myeloid colony formation. IL-3 induces early myeloid progenitors and a more developed myeloid progenitor, the granulocyte-macrophage colony-forming unit (GM-CFU), to multiply and develop into mature myeloid cells. GM-CSF induces GM-CFU to become mature myeloid cells, while IL-5 induces eosinophil progenitors to become mature eosinophils. Stem Cell Factor (SCF) + IL-6 and FLT3 ligand, which have no effect on colony formation by themselves, were used to enhance the effects of IL-3 and GM-CSF, respectively. We found that thermal injury increased the number of early myeloid progenitors and GM-CFU in the spleen with either IL-3 or GM-CSF as a stimulant. Thermal injury increased the number of early myeloid progenitors in the bone marrow when GM-CSF, but not IL-3, was used to stimulate colony growth. Also, thermal injury increased the numbers of eosinophil progenitors in rat spleen and bone marrow and increased splenic levels of IL-5 mRNA. Author Affiliation: (1) Shriners Hospital for Children, Cincinnati, OH (2) Department of Surgery, University of Cincinnati, Cincinnati, OH Article History: Registration Date: 17/10/2004

Byline: K. Hara (1), T. Hasegawa (1), H. Ooi (1), T. Koya (1), Y. Tanabe (1), H. Tsukada (1), K. Igarashi (1), E. Suzuki (1), M. Arakawa (1), F. Gejyo (1) Keywords: Key words: Eosinophil--Transforming growth factor [beta]--Plasmin--Plasminogen activator--Bronchial asthma. Abstract: Eosinophilic bronchitis is an essential component of bronchial asthma, and eosinophils play an important role. We studied the effect of eosinophils on cell surface plasmin generation by bronchial epithelial cells, because plasmin is thought to be involved in bronchial tissue repair/remodeling by means of fibrinolysis and the activation of proteases such as matrix metalloproteases. Plasmin was generated from exogenous plasminogen on the cell surface of cultured bronchial epithelial cells, NCI-H292. Transforming growth factor [beta] (TGF-[beta]) treatment resulted in reduced cell surface plasmin generation and a large increase in plasminogen activator inhibitor-type 1 (PAI-1) antigen production in NCI-H292 cells, whereas no conspicuous effects were observed with IL-1[beta] and TNF[alpha] treatment (regulators in pulmonary epithelial cells). On the other hand, this cell surface plasmin generation was reduced by co-incubation with Eol-1, an eosinophil cell line. The addition of TGF-[beta] antisense and anti-TGF-[beta] antibodies attenuated this adverse effect of Eol-1 cell co-incubation. These data suggest that eosinophils play an inhibitory role on cell surface plasmin generation by bronchial epithelial cells by means of the up-regulation of PAI-1 expression induced by TGF-[beta]. Therefore, the accumulation of eosinophils in bronchial walls is thought to be involved in bronchial tissue repair/remodeling in asthma through this protease network. Author Affiliation: (1) Department of Medicine (II), Niigata University School of Medicine, Niigata, Japan, JP Article note: Accepted for publication: 10 January 2001

Byline: David M. Hammerbeck (1), Sean M. Mcgurran (1), Pam L. Radziszewski (1), Elaine A. Egging (1), David D. Johnson (1), Ann M. Hupperts (1), Gary W. Gullikson (1) Abstract: Representative glucocorticosteroids (GCS) and phosphodiesterase IV (PDE4) inhibitors were compared in several models of pulmonary inflammation ranging in severity. Lung tissue eosinophil peroxidase (EPO) levels rather than bronchoalveolar lavage fluid (BALF) EPO or eosinophil percentages were used to indicate eosinophil recruitment after intratracheal instillation of sephadex beads in rats or nebulized ovalbumin in sensitized guinea pigs. A single oral or intratracheal administration of a GCS was effective against mild and robust sephadex-induced eosinophilia whereas the PDE.sub.4 inhibitors evaluated appeared more effective in the milder sephadex models. The GCS were also more effective against sephadex-induced than ovalbumin-induced eosinophilia. The effectiveness of the GCS and PDE.sub.4 inhibitors improved when the severity of the ovalbumin-induced eosinophilia was decreased. Multiple day dosing also improved activity. These studies indicated that activity was influenced greatly by administration protocols, the severity of the inflammatory response and possibly the method used for estimating eosinophil recruitment. Author Affiliation: (1) 3M Pharmaceuticals, 3M Company, St. Paul, Minnesota, 55144 Article History: Registration Date: 09/10/2004

Byline: Eva Fernvik (1), Joachim Lundahl (1), Gunilla Hallden (1) Abstract: Eosinophils accumulate at sites of allergic inflammation, and play important roles in asthma/allergic disorders. The mechanism of eosinophil recruitment into tissues is not fully understood. In this study, we evaluated whether adhesion and/or transmigration, in the presence of IL-5 and eotaxin, alter the expression of CD9, CD11b, the [beta].sub.1[alpha].sub.4-integrin, and the EG2-epitope on intracellular ECP. We also investigated whether CD9 is involved in the adhesion process. With flow cytometry the surface expression of CD9, CD11b and the [beta].sub.1[alpha].sub.4-integrin, and the intracellular expression of EG2, were analyzed before, and after transmigration/adhesion to fibronectin. To evaluate the eventual role of CD9 in adhesion, eosinophils were preincubated with monoclonal antibodies to CD9. We observed decreased expression of CD9, and increased expression of CD11b on eosinophils, after adhesion and transmigration. The transmigration did not change the expression of the [beta].sub.1[alpha].sub.4-integrin or EG2, whereas the adhesion resulted in a decreased EG2 expression. Antibodies to CD9 decreased the adhesion property of eosinophils. The eosinophils are activated after both adhesion and transmigration by means of decreased CD9 and increased CD11b expression. The expression of the EG2-epitope on intracellular ECP was decreased when eosinophils adhered to fibronectin, probably due to degranulation. Our results also indicate that CD9 is involved in the adhesion of eosinophils to fibronectin. Author Affiliation: (1) Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska Hospital and Institute, Stockholm, Sweden Article History: Registration Date: 09/10/2004

Byline: S. Lantero (1), S. Oddera (1), M. Silvestri (1), R. Gonzalez Rodriguez (1), M. C. Morelli (2), G. A. Rossi (1) Keywords: Key words: Allergic asthma--T-lymphocytes--Cytokines--Granulocytes--Chemotaxis--Interleukin-5--Corticosteroids. Abstract: Treatment of allergic asthma with inhaled corticosteroids results in local down-regulation of proinflammatory cytokine synthesis and in marked decrease in tissue eosinophilia. Blood concentrations of inhaled corticosteroids, although significantly lower than those measured in the lung, may still have antiinflammatory effects on circulating eosinophils, reducing their ability to migrate. The aim of our study was to evaluate in vitro the activity of budesonide on blood eosinophils by measuring their chemotactic response, eosinophil cationic protein (ECP) release, and hydrogen peroxide ([H.sub.2]O.sub.2) production in the presence of different drug concentrations similar to those obtained at airway level (10.sup.-8 and 10.sup.-7 M) and at blood level (10.sup.-10 and 10.sup.-9 M). Partially purified blood eosinophils, isolated from 23 asthmatic subjects, were used to evaluate the activity of budesonide on: (1) chemotaxis toward the activated fifth component of complement (C5a, 0.1 ug/ml) or recombinant human (rh) interleukin (IL)-5 (200 pg/ml), (2) ECP release by cells stimulated with tetradecanoylphorbol acetate (TPA) and (3) [H.sub.2]O.sub.2 production by TPA-activated cells. The chemotactic response to C5a was down-regulated significantly by budesonide only by the highest concentrations tested (10.sup.-8 and 10.sup.-7 M) differently, budesonide was effective in inhibiting eosinophil migration toward rhIL-5, at all concentrations tested (p &lt 0.01, each comparison). By contrast, no drug-induced modifications were observed in ECP release or in [H.sub.2]O.sub.2 production (p &gt 0.05, each comparison). We conclude that concentrations of budesonide similar to those obtained in vivo are effective in inhibiting eosinophil locomotion but not in down-regulating the release of reactive oxygen species and granule-associated proteins. Author Affiliation: (1) Pulmonary Division, G. Gaslini Institute, Genoa, Italy, IT (2) Astra Farmaceutici, Milan, Italy, IT Article note: Accepted for publication: 11 February 1999

Byline: S. Oddera (1), M. Silvestri (1), R. Penna (2), G. Galeazzi (2), E. Crimi (3), G. A. Rossi (1) Keywords: Key words: Eosinophils--Eosinophil cationic protein--Asthma--Atopy--Bronchial hyperresponsiveness--Methacholine--Bronchoalveolar lavage--Inflammation. Abstract: Allergen exposure in atopic asthmatic patients is associated with recruitment and activation of eosinophils in the airways. Once activated, eosinophils release toxic products, including the eosinophil cationic protein (ECP), able to damage bronchial structures and to increase bronchial hyperresponsiveness. With this background, the present study was designed to evaluate whether ECP levels in bronchoalveolar lavage (BAL) fluid could reflect, better than BAL eosinophil counts, the cellular activation that follows allergen exposure in atopic asthmatics. Twenty-two atopic patients attended the laboratory on two separate days. On the 1st day, they underwent methacholine (MCh) inhalation challenge to detect the degree of nonspecific bronchial hyperresponsiveness. On the 2nd day, they underwent fiberoptic bronchoscopy and BAL, at baseline or 4--6 h after allergen inhalation challenge. In this latter patient group, MCh challenge was repeated 3--5 h after allergen challenge, 1 h before fiberoptic bronchoscopy. The analysis of the mean baseline FEV.sub.1 values and the degree of bronchial reactivity to MCh (MCh Pd.sub.20) on the 1st study day did not demonstrate differences between the two patient groups (p &gt 0.1, each comparison). In addition, in the allergen-challenged group, MCh Pd.sub.20 was decreased significantly after allergen challenge (151.4 ug/ml and 67.6 ug/ml, respectively, before and after challenge p &lt 0.05). Evaluation of the different BAL cell types demonstrated that the proportions of eosinophils and epithelial cells were increased significantly in the allergen-challenged group compared with the group evaluated at baseline (p &lt 0.01 and p &lt 0.05, respectively). Moreover, ECP levels, corrected by the correspondent albumin levels (ECP/Alb), were higher in the allergen-challenged group compared with the group evaluated at baseline (p &lt 0.05). In addition, although a positive correlation was demonstrated between BAL eosinophil percentages and ECP/Alb values (r= 0.72, p &lt 0.05) in the group evaluated at baseline, no links were found between these parameters in the allergen-challenged group (p &gt 0.1). However, in this latter group, a weak positive correlation was demonstrated between eosinophil percentages and IMch, i.e., the increased nonspecific bronchial reactivity, which is observed after allergen challenge (r= 0.55 p &lt 0.05). Thus, in stable asthmatic patients an ongoing activation of eosinophils parallels their migration, but this eosinophilic inflammation is not strictly related to bronchial reactivity to Mch. By contrast, after allergen inhalation challenge, eosinophil recruitment and activation seem to follow different temporal kinetics, and eosinophilic inflammation may be partially associated with the degree of airway hyperresponsiveness. Author Affiliation: (1) Divisione di Pneumologia, Istituto G. Gaslini, Universita di Genova, Genova, Italy, IT (2) Laboratorio di Analisi, Istituto G. Gaslini, Universita di Genova, Genova, Italy, IT (3) Cattedra di Fisiopatologia Respiratoria, Universita di Genova, Genova, Italy, IT Article note: Accepted for publication: 15 September 1997

Byline: Joachim Lundahl (1), Ali Moshfegh (1), Reidar Gronneberg (2), Gunilla Hallden (1) Abstract: 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. Author Affiliation: (1) Department of Laboratory Medicine, Division of Clinical Immunology, Karolinska Hospital, Sweden (2) Department of Medicine, Division of Respiratory and Allergic Diseases, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden Article History: Registration Date: 03/10/2004

Byline: H. L. Tan (1,2), N. Sithasanan (2), P. Foley (2), G. P. Davidson (3) Keywords: Eosinophilic gastroenteritis; Duodenal strictures; Medical management of eosinophilic gastroenteritis Abstract: Eosinophilic gastroenteritis is an uncommon condition of unknown etiology that has only been relatively recently reported. Its clinical manifestations range from a mild disease to more severe forms resembling Crohn's disease. Enteric strictures are a rare but recognized complication of this condition. We report a case of eosinophilic gastroenteritis in an infant presenting with severe duodenal strictures that was successfully managed with oral prednisolone. We believe that this is the first reported case of duodenal strictures secondary to eosinophilic gastroenteritis. Author Affiliation: (1) Department of Paediatrics, Adelaide University, 5006, Adelaide, Australia (2) Department of Paediatric Surgery, Adelaide University, 5006, Adelaide, Australia (3) Department of Gastroenterology, Women's and Children's Hospital, , 5006, Adelaide, Australia Article History: Accepted Date: 23/09/2002 Online Date: 02/08/2003