Mouse Models of Eosinophil-Associated Lung Dysfunction

Project: Research project

Project Details

Description

Mouse models of respiratory inflammation have been indispensable to the dissection
of immune pathways that result in lung remodeling and dysfunction. The value of these models results not only
from their ability to represent the inflammation occurring in human disease but also from their usefulness in
reductionist approaches examining specific cells and/or inflammatory pathways. Previous attempts using mice
to examine the role of eosinophils in respiratory inflammation have been limited by the nominal character of
disease pathology occurring in these models (i.e., the observed pathologies are only a subset of those
occurring in humans) as well as differences observed between eosinophil activities occurring in the lungs of
asthma patients and those in the established mouse models (i.e., eosinophils in these models displayed little
evidence of granule protein release (i.e., degranulation)). These limitations have led us to create an allergennaive
double transgenic mouse (I5/hE2) that expresses IL-5 systemically from mature T cells and eotaxin-2
locally from lung epithelial cells. I5/hE2 mice develop many pulmonary pathologies that were absent in earlier
mouse models but which nonetheless occur in severe asthma patients. More importantly, extensive eosinophil
degranulation in the lung (previously only associated with asthma patients) accompanies the pathologies in the
I5/hE2 model. In addition, we have demonstrated that all of the pathologies in I5/hE2 mice are absolutely
dependent on the induced pulmonary eosinophilia. This proposal capitalizes on the availability of the I5/hE2
transgenic model as well as our unique eosinophil-less line of mice (PHIL) to test the central hypothesis that
eosinophils themselves are the relevant source of the molecules commonly suggested to be
responsible for remodeling and airway dysfunction. The objectives of the proposal will be achieved using
these mice and other novel eosinophil-specific reagents/methodologies by the completion of the following
Specific Aims: (1) To determine if immunoregulation of the pulmonary microenvironment by eosinophils
contributes to remodeling events and lung dysfunction; (2) To define the role(s) of eosinophil-mediated
leukotrienes activities in the development of inflammatory changes in the lung; (3) To determine the
importance of eosinophil-dependent TGF-[unreadable]1 expression and activation in remodeling and lung dysfunction; (4)
To define the pulmonary pathologies mediated by the release of eosinophil cationic granule proteins.
StatusNot started

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