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Coexpression of IL-5 and Eotaxin-2 in Mice Creates an Eosinophil-Dependent Model of Respiratory Inflammation with Characteristics of Severe Asthma¹

Sergei I. Ochkur^*, Elizabeth A. Jacobsen^*, Cheryl A. Protheroe^*, Travis L. Biechele, Ralph S. Pero, Michael P. McGarry^*, Huiying Wang, Katie R. O’Neill, Dana C. Colbert, Thomas V. Colby, Huahao Shen, Michael R. Blackburn^¶, Charles C. Irvin^||, James J. Lee^2,* and Nancy A. Lee^2,

^* Division of Pulmonary Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, AZ 85259; Division of Hematology/Oncology, Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, AZ 85259; Department of Respiratory Medicine, Second Hospital, Zhejiang University College of Medicine, HangZhou, People’s Republic of China; Department of Laboratory Medicine/Pathology, Mayo Clinic Arizona, Scottsdale, AZ 85259; ^¶ Department of Biochemistry and Molecular Biology, University of Texas Houston Health Science Center, Houston, TX 77030; and ^|| Vermont Lung Center, Department of Medicine, University of Vermont, Burlington, VT 05405

Mouse models of allergen provocation and/or transgenic gene expression have provided significant insights regarding the cellular, molecular, and immune responses linked to the pathologies occurring as a result of allergic respiratory inflammation. Nonetheless, the inability to replicate the eosinophil activities occurring in patients with asthma has limited their usefulness to understand the larger role(s) of eosinophils in disease pathologies. These limitations have led us to develop an allergen-naive double transgenic mouse model that expresses IL-5 systemically from mature T cells and eotaxin-2 locally from lung epithelial cells. We show that these mice develop several pulmonary pathologies representative of severe asthma, including structural remodeling events such as epithelial desquamation and mucus hypersecretion leading to airway obstruction, subepithelial fibrosis, airway smooth muscle hyperplasia, and pathophysiological changes exemplified by exacerbated methacholine-induced airway hyperresponsiveness. More importantly, and similar to human patients, the pulmonary pathologies observed are accompanied by extensive eosinophil degranulation. Genetic ablation of all eosinophils from this double transgenic model abolished the induced pulmonary pathologies, demonstrating that these pathologies are a consequence of one or more eosinophil effector functions.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Mayo Foundation and grants from the National Institutes of Health HL065228 and K26-RR019709 (to J.J.L.) HL058723 (to N.A.L.), and National Center for Research Resources-Centers of Biomedical Research Excellence P20RR15557, P01-HL67004, and HL-EB67273 (to C.C.I.). Additional support was provided by American Heart Association Grants 045580Z (to J.J.L.) and 0555639Z (to N.A.L.) and Respiratory Postdoctoral Training Grant HL07897 (to S.I.O. and E.A.J.).

² Address correspondence and reprint requests to Dr. Nancy A. Lee or Dr. James J. Lee, S. C. Johnson Medical Research Center, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ 85259; E-mail addresses: nlee{at}mayo.edu or jjlee{at}mayo.edu

³ Abbreviations used in this paper: MBP, major basic protein; EPO, eosinophil peroxidase; EEF, eosinophil effector function; BAL, bronchoalveolar lavage; RT, room temperature; PAS, periodic-acid Schiff; AHR, airway hyperresponsiveness.

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