Coexpression of IL-5 and eotaxin-2 in mice creates an eosinophil-dependent model of respiratory inflammation with characteristics of severe asthma

被引:111
作者
Ochkur, Sergei I.
Jacobsen, Elizabeth A.
Protheroe, Cheryl A.
Biechele, Travis L.
Pero, Ralph S.
McGarry, Michael P.
Wang, Huiying
O'Neill, Katie R.
Colbert, Dana C.
Colby, Thomas V.
Shen, Huahao
Blackburn, Michael R.
Irvin, Charles C.
Lee, James J.
Lee, Nancy A.
机构
[1] Mayo Clin Arizona, SC Johnson Med Res Ctr, Div Pulm Med, Dept Biochem & Mol Biol, Scottsdale, AZ 85259 USA
[2] Mayo Clin Arizona, Div Hematol Oncol, Dept Biochem & Mol Biol, Scottsdale, AZ 85259 USA
[3] Zhejiang Univ, Coll Med, Dept Resp Med, Hosp 2, Hangzhou, Peoples R China
[4] Mayo Clin Arizona, Dept Lab Med Pathol, Scottsdale, AZ 85259 USA
[5] Univ Texas, Ctr Hlth Sci, Dept Biochem & Mol Biol, Houston, TX 77030 USA
[6] Univ Vermont, Dept Med, Vermont Lung Ctr, Burlington, VT 05405 USA
关键词
D O I
10.4049/jimmunol.178.12.7879
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 transge nic 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.
引用
收藏
页码:7879 / 7889
页数:11
相关论文
共 50 条
  • [1] Metabolic consequences of adenosine deaminase deficiency in mice are associated with defects in alveogenesis, pulmonary inflammation, and airway obstruction
    Blackburn, MR
    Volmer, JB
    Thrasher, JL
    Zhong, HY
    Crosby, JR
    Lee, JJ
    Kellems, RE
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2000, 192 (02) : 159 - 170
  • [2] Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis
    Blanchard, C
    Wang, N
    Stringer, KF
    Mishra, A
    Fulkerson, PC
    Abonia, JP
    Jameson, SC
    Kirby, C
    Konikoff, MR
    Collins, MH
    Cohen, MB
    Akers, R
    Hogan, SP
    Assa'ad, AH
    Putnam, PE
    Aronow, BJ
    Rothenberg, ME
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 2006, 116 (02) : 536 - 547
  • [3] Degranulation of eosinophils mediated by intercellular adhesion molecule-1 and its ligands is involved in adhesion molecule expression on endothelial cells-selective induction of VCAM-1
    Chihara, J
    Yamamoto, T
    Kayaba, H
    Kakazu, T
    Kurachi, D
    Yamamoto, J
    Iwasa, S
    Iida, K
    Urayama, O
    Kobayashi, Y
    [J]. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 1999, 103 (05) : S452 - S456
  • [4] Eosinophil degranulation in the allergic lung of mice primarily occurs in the airway lumen
    Clark, K
    Simson, L
    Newcombe, N
    Koskinen, AML
    Mattes, J
    Lee, NA
    Lee, JJ
    Dent, LA
    Matthaei, KI
    Foster, PS
    [J]. JOURNAL OF LEUKOCYTE BIOLOGY, 2004, 75 (06) : 1001 - 1009
  • [5] Colby TV, 1998, AM J CLIN PATHOL, V109, P101
  • [6] Eosinophil major basic protein-1 does not contribute to allergen-induced airway pathologies in mouse models of asthma
    Denzler, KL
    Farmer, SC
    Crosby, JR
    Borchers, M
    Cieslewicz, G
    Larson, KA
    Cormier-Regard, S
    Lee, NA
    Lee, JJ
    [J]. JOURNAL OF IMMUNOLOGY, 2000, 165 (10) : 5509 - 5517
  • [7] Extensive eosinophil degranulation and peroxidase-mediated oxidation of airway proteins do not occur in a mouse ovalbumin-challenge model of pulmonary inflammation
    Denzler, KL
    Borchers, MT
    Crosby, JR
    Cieslewicz, G
    Hines, EM
    Justice, JP
    Cormier, SA
    Lindenberger, KA
    Song, W
    Wu, WJ
    Hazen, SL
    Gleich, GJ
    Lee, JJ
    Lee, NA
    [J]. JOURNAL OF IMMUNOLOGY, 2001, 167 (03) : 1672 - 1682
  • [8] DVORAK AM, 1994, HISTOL HISTOPATHOL, V9, P339
  • [9] New insights into the pathogenesis of asthma
    Elias, JA
    Lee, CG
    Zheng, T
    Ma, B
    Homer, RJ
    Zhu, Z
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 2003, 111 (03) : 291 - 297
  • [10] Cytolysis and piecemeal degranulation as distinct modes of activation of airway mucosal eosinophils
    Erjefält, JS
    Andersson, M
    Greiff, L
    Korsgren, M
    Gizycki, M
    Jeffery, PK
    Persson, GA
    [J]. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 1998, 102 (02) : 286 - 294