Co-expression of eotaxin-2 and IL-5 in double transgenic mice leads to eosinophil degranulation and the development of pulmonary pathologies

Abstract Rationale The refractory character of mouse eosinophils with respect to activation/degranulation has limited the utility of these animals as models of eosinophil effector functions ( EEFs ) in the lung and, therefore, human diseases. The effects of ectopic expression of both IL-5 and eotaxin-2 were assessed to develop a model system that duplicates the EEFs that occur in the lungs of asthma patients. Methods The effects of eotaxin-2 and IL-5 were assessed either through intratracheal instillation in OVA-treated mice or by constitutive expression in transgenic animals. Results Instillation of either eotaxin-1 or -2 into the lungs of OVA-treated mice results in eosinophil degranulation and the release of secondary granule proteins. The observed effects of eotaxin-2 were particularly significant. Constitutive expression of either eotaxin-2 or IL-5 in transgenic mice had limited, but defined, effect on the lung, including a nominal tissue eosinophilia without an increase in BAL eosinophils or induced histopathology. Nonetheless, mice of each line displayed altered airway responses to methacholine. In contrast, transgenic mice expressing both IL-5 and eotaxin-2 developed a dramatic tissue and airway eosinophilia. This eosinophilia was also accompanied by evidence of degranulation and the release of secondary granule proteins as well as equally dramatic pulmonary histopathologies and lung dysfunction. Conclusions The synergistic effect of expressing both eotaxin-2 and IL-5 leads to the recruitment/activation of eosinophils and, in turn, to pulmonary pathologies. These data suggest that lung EEFs may require both stimuli and that these activities may contribute to pulmonary pathologies.