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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: 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: 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: 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