A new murine model of persistent lung eosinophilic inflammation

Abstract

Key words: asthma -late-phase reaction -eosinophil -mice -eosinophil peroxidase Asthma is a chronic inflammatory disease of the airways and its incidence is increasing in urban environments. It is characterized by intermittent, reversible airway obstruction and by bronchial hyperreactivity. Nearly a century ago it was observed that eosinophils are the major cell type infiltrating into the airways of asthmatic patients (Ellis 1908). Based on data obtained in animal models of asthma, it has been proposed that T cellderived cytokines, namely IL-4 and IL-5, play a central role in the induction of lung eosinophilic inflammation. IL-4 is a key cytokine for IgG1 and IgE isotype switching (Drazen et al. 1996), whereas IL-5 is required for the mobilization and migration of eosinophils to the lung (Walker et al. 1991, Nakajima et al. 1992). Indeed, it was shown that IL-4 or IL-5 knockout mice immunized with ovalbumin failed to develop airway hyperresponsiveness after OVA aerosol challenge (Corry et al. 1996, Foster et al. 1996. Major advances in the understanding of the mechanisms involved in the pathogenesis of asthma came from studies using animal models. A great variety of experimental models have been developed; most of them involve immunization with adjuvants, usually Alum and multiple antigen boosters.We have recently reported that immunization of mice with a subcutaneous implant of fragments of heat-coagulated chicken egg white (EWI) without adjuvant was able to induce a typical late-phase reaction with a prominent eosinophilic infiltrate after ovalbumin challenge into the footpad . We have then adapted this model to induce a late-phase reaction in mouse lungs. For this, mice were immunized with EWI implanted into the subcutaneous tissue and challenged with heat aggregated OVA instilled into the trachea 14 days later. It was found that 48 hr after challenge a high percentage of eosinophils was found in the BAL (35%) and increased levels of EPO activity were found in lung homogenates. These results were reproduced in five different mouse strains. Compared to another five models of lung hypersensitivity, the EWI model was the only one to induce eosinophilia which persisted for 30 days. The histopathological findings confirmed the intense eosinophilia and resembled those of human asthma .In this study we have further characterized this model by analyzing: (a) the efficacy of challenge with aerosolized ovalbumin, (b) the effect of immunization with different concentrations of chicken egg white antigens on airway and bone marrow eosinophilia and (c) the isotypic profile of antibody production. More importantly, we outline the main characteristics of this new experimental model of asthma. MATERIALS AND METHODSImmunizations protocols for the induction of pulmonary eosinophilia -Group of B6 mice were immunized with 100 µg OVA (grade III, Sigma Chemical Co.) adsorbed to 1.4 mg of alum (OVAAlum) injected intraperitoneally or with a fragment of solidified chicken egg white (EWI) implanted subcutaneously in the dorsal flank of...

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Leukotriene B4 is essential for selective eosinophil recruitment following allergen challenge of CD4+ cells in a model of chronic eosinophilic inflammation

“…This model involves surgical implantation of a piece of heat-coagulated hen egg white, which is followed by chronic, intense eosinophilic inflammation at the implant site, accompanied by a large increase in bone-marrow eosinophilopoiesis lasting several weeks (Xavier Elsas et al, 2004). EWI carriers, when challenged with ovalbumin in the airways, develop asthma-like manifestations, associated with intense eosinophil infiltration (Carvalho et al, 1999;Siqueira et al, 1997;Russo et al, 1997). Although much remains to be established concerning the mechanisms of this peculiar type of inflammatory reaction, it is clearly dependent on a protein antigen (ovalbumin), which must be administered in large amounts, although in insoluble form, which ensures a long half-life at the implant site.…”

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