title: Eosinophils and CCR3 regulate interleukin-13 transgene-induced pulmonary remodeling.
abstract: 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 (Deltadbl-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-beta1 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.
authors.affiliation: Deparmtnet of Molecular Genetics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Ave., MLC 7028, Cincinnati, OH 45229, USA.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Fulkerson
authors.forename: Christine A
authors.initials: CA
authors.lastname: Fischetti
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
mesh_terms: D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004804:Eosinophils / Q000502:physiology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000235:genetics / Q000502:physiology*; D008024:Ligands; D008168:Lung / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009093:Mucus / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D011657:Pulmonary Eosinophilia / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000378:metabolism* / Q000502:physiology
chemical_list: C515457:Ccl11 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D018793:Interleukin-13; D008024:Ligands; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D003094:Collagen; D010447:Peptide Hydrolases