Lung Pathologies in a Chronic Inflammation Mouse Model are Independent of Eosinophil Degranulation.

The release of eosinophil granule proteins in the lungs of asthma patients has been dogmatically linked with lung remodeling and airway hyperresponsiveness (AHR). However, the demonstrated inability of established mouse models to display the eosinophil degranulation occurring in human subjects has prevented a definitive in vivo test of this hypothesis.,To demonstrate in vivo causative links between induced pulmonary histopathologies/lung dysfunction and eosinophil degranulation.,A transgenic mouse model of chronic Th2 driven inflammation overexpressing IL-5 from T cells and human eotaxin 2 in the lung (I5/hE2) was used to test the hypothesis that chronic histopathologies and the development of AHR occur as a consequence of extensive eosinophil degranulation in the lung parenchyma.,Studies targeting specific inflammatory pathways in I5/hE2 mice surprisingly showed that eosinophil-dependent immunoregulative events and not the release of individual secondary granule proteins are the central contributors to Th2-induced pulmonary remodeling and lung dysfunction. Specifically, our studies highlighted a significant role for eosinophil-dependent IL-13 expression. In contrast, extensive degranulation leading to the release of MBP-1 or EPX was not causatively linked to many of the induced pulmonary histopathologies. However, these studies did define a previously unappreciated link between the release of EPX (but not MBP-1) and observed levels of induced airway mucin.,These data suggest that improvements observed in asthma patients responding to therapeutic strategies ablating eosinophils may occur as a consequence of targeting immunoregulatory mechanisms and not by simply eliminating the destructive activities of these purportedly end-stage effector cells.