Coexpression of IL-5 and eotaxin-2 in mice creates an eosinophil-dependent model of respiratory inflammation with characteristics of severe asthma.
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.
Ochkur
Sergei I
SI
Division of Pulmonary Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA.
Jacobsen
Elizabeth A
EA
Protheroe
Cheryl A
CA
Biechele
Travis L
TL
Pero
Ralph S
RS
McGarry
Michael P
MP
Wang
Huiying
H
O'Neill
Katie R
KR
Colbert
Dana C
DC
Colby
Thomas V
TV
Shen
Huahao
H
Blackburn
Michael R
MR
Irvin
Charles C
CC
Lee
James J
JJ
Lee
Nancy A
NA
D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002465:Cell Movement; D054423:Chemokine CCL24; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D047209:Eosinophil Peroxidase / Q000032:analysis; D004804:Eosinophils / Q000000981:diagnostic imaging / Q000201:enzymology / Q000276:immunology*; D006801:Humans; D015848:Interleukin-5 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011014:Pneumonia / Q000235:genetics / Q000276:immunology; D011657:Pulmonary Eosinophilia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D014463:Ultrasonography
C515484:CCL24 protein, human; C515485:Ccl24 protein, mouse; D054423:Chemokine CCL24; D019742:Chemokines, CC; D015848:Interleukin-5; D047209:Eosinophil Peroxidase