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(American Journal of Pathology. 2006;169:2117-2126.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060617

Eosinophils and CCR3 Regulate Interleukin-13 Transgene-Induced Pulmonary Remodeling

Patricia C. Fulkerson*, Christine A. Fischetti{dagger} and Marc E. Rothenberg{dagger}

From the Departments of Molecular Genetics, Biochemistry, and Microbiology,* and the Division of Allergy and Immunology,{dagger} Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio

Interleukin (IL)-13 transgene overexpression in the lung induces features of chronic inflammatory lung disorders, including an eosinophil-rich inflammatory cell infiltration, airway hyper-reactivity, and remodeling of the airway (eg, subepithelial fibrosis, goblet cell metaplasia, and smooth muscle hypertrophy and hyperplasia). Here, we aimed to define the role of eosinophils and eosinophil signaling molecules [eg, eotaxins and CC chemokine receptor (CCR) 3] in IL-13-mediated airway disease. To accomplish this, we mated IL-13-inducible lung transgenic mice with mice deficient in eosinophil chemoattractant molecules (eotaxin-1, eotaxin-2, and their receptor CCR3) and with mice genetically deficient in eosinophils ({Delta}dbl-GATA). We report that in the absence of eotaxin-2 or CCR3, there was a profound reduction in IL-13-induced eosinophil recruitment into the lung lumen. In contrast, in the absence of eotaxin-1, there was a fourfold increase in IL-13-mediated eosinophil recruitment into the airway. IL-13 transgenic mice deficient in CCR3 had a 98% reduction in lung eosinophils. Furthermore, the reduction in pulmonary eosinophils correlated with attenuation in IL-13-induced mucus cell metaplasia and collagen deposition. Mechanistic analysis identified alterations in pulmonary protease and transforming growth factor-ß1 expression in eosinophil-deficient mice. Taken together, these data definitively identify a functional contribution by eosinophils on the effects of chronic IL-13 expression in the lung.




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