title: Lung Pathologies in a Chronic Inflammation Mouse Model Are Independent of Eosinophil Degranulation.
abstract: The release of eosinophil granule proteins in the lungs of patients with asthma has been dogmatically linked with lung remodeling and airway hyperresponsiveness. However, the demonstrated inability of established mouse models to display the eosinophil degranulation occurring in human subjects has prevented a definitive in vivo test of this hypothesis.
  
  
  
  To demonstrate in vivo causative links between induced pulmonary histopathologies/lung dysfunction and eosinophil degranulation.
  
  
  
  A transgenic mouse model of chronic T-helper cell type 2-driven inflammation overexpressing IL-5 from T cells and human eotaxin 2 in the lung (I5/hE2) was used to test the hypothesis that chronic histopathologies and the development of airway hyperresponsiveness occur as a consequence of extensive eosinophil degranulation in the lung parenchyma.
  
  
  
  Studies targeting specific inflammatory pathways in I5/hE2 mice surprisingly showed that eosinophil-dependent immunoregulative events and not the release of individual secondary granule proteins are the central contributors to T-helper cell type 2-induced pulmonary remodeling and lung dysfunction. Specifically, our studies highlighted a significant role for eosinophil-dependent IL-13 expression. In contrast, extensive degranulation leading to the release of major basic protein-1 or eosinophil peroxidase was not causatively linked to many of the induced pulmonary histopathologies. However, these studies did define a previously unappreciated link between the release of eosinophil peroxidase (but not major basic protein-1) and observed levels of induced airway mucin.
  
  
  
  These data suggest that improvements observed in patients with asthma responding to therapeutic strategies ablating eosinophils may occur as a consequence of targeting immunoregulatory mechanisms and not by simply eliminating the destructive activities of these purportedly end-stage effector cells.
authors.affiliation: 1 Division of Pulmonary Medicine and.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Jacobsen
authors.affiliation: 1 Division of Pulmonary Medicine and.
authors.forename: Sergei I
authors.initials: SI
authors.lastname: Ochkur
authors.affiliation: 1 Division of Pulmonary Medicine and.
authors.forename: Alfred D
authors.initials: AD
authors.lastname: Doyle
authors.affiliation: 1 Division of Pulmonary Medicine and.
authors.forename: William E
authors.initials: WE
authors.lastname: LeSuer
authors.affiliation: 2 Department of Medicine, Guizhou Provincial People's Hospital, Guizhou, China; and.
authors.forename: Wen
authors.initials: W
authors.lastname: Li
authors.affiliation: 3 Division of Hematology/Oncology, Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, Arizona.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Protheroe
authors.affiliation: 3 Division of Hematology/Oncology, Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, Arizona.
authors.forename: Dana
authors.initials: D
authors.lastname: Colbert
authors.affiliation: 1 Division of Pulmonary Medicine and.
authors.forename: Katie R
authors.initials: KR
authors.lastname: Zellner
authors.affiliation: 2 Department of Medicine, Guizhou Provincial People's Hospital, Guizhou, China; and.
authors.forename: HuaHao H
authors.initials: HH
authors.lastname: Shen
authors.affiliation: 4 Vermont Lung Center, Department of Medicine, University of Vermont, Burlington, Vermont.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Irvin
authors.affiliation: 1 Division of Pulmonary Medicine and.
authors.forename: James J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: 3 Division of Hematology/Oncology, Department of Biochemistry and Molecular Biology, Mayo Clinic Arizona, Scottsdale, Arizona.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Lee
mesh_terms: D000818:Animals; D054423:Chemokine CCL24 / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D004804:Eosinophils / Q000378:metabolism*; D005434:Flow Cytometry; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D015848:Interleukin-5 / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018418:Th2 Cells / Q000378:metabolism
chemical_list: D054423:Chemokine CCL24; D015848:Interleukin-5
keywords: asthma; chronic inflammation; eosinophil peroxidase; lung; major basic protein