title: Obligatory role for interleukin-13 in obstructive lesion development in airway allografts.
abstract: The pathogenesis of bronchiolitis obliterans (BO), a common and devastating obliterative disorder of small airways following lung transplantation, remains poorly understood. Lesions are characterized in their early stages by lymphocyte influx that evolves into dense fibrotic infiltrates. Airway specimens taken from patients with histological BO revealed infiltrating myofibroblasts, which strongly expressed the signaling chain of the high affinity interleukin-13 (IL-13) receptor IL-13Ralpha1. Because IL-13 has proinflammatory and profibrotic actions, a contributory role for IL-13 in BO development was examined using murine models of orthotopic and heterotopic tracheal transplantation. Compared with airway isografts, allografts exhibited a significant increase in relative IL-13 mRNA and protein levels. Allogeneic tracheas transplanted into IL-13-deficient mice were protected from BO in both transplant models. Flow cytometric analysis of orthotopic transplant tissue digests revealed markedly fewer infiltrating mononuclear phagocytes and CD3(+) T lymphocytes in IL-13-deficient recipients. Furthermore, protection from luminal obliteration, collagen deposition, and myofibroblast infiltration was observed in heterotopic airways transplanted into the IL-13(-/-) recipients. Transforming growth factor-beta1 expression was significantly decreased in tracheal allografts into IL-13(-/-) recipients, compared to wild-type counterparts. These human and murine data implicate IL-13 as a critical effector cytokine driving cellular recruitment and subsequent fibrosis in clinical and ex-perimental BO.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, 1150 W. Medical Center Drive, Ann Arbor, MI 48109-0644, USA. vlama@umich.edu
authors.forename: Vibha N
authors.initials: VN
authors.lastname: Lama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Harada
authors.forename: Linda N
authors.initials: LN
authors.lastname: Badri
authors.forename: Andrew
authors.initials: A
authors.lastname: Flint
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
authors.forename: Andrew
authors.initials: A
authors.lastname: McKenzie
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
authors.forename: Galen B
authors.initials: GB
authors.lastname: Toews
authors.forename: Bethany B
authors.initials: BB
authors.lastname: Moore
authors.forename: David J
authors.initials: DJ
authors.lastname: Pinsky
mesh_terms: D000328:Adult; D000818:Animals; D001989:Bronchiolitis Obliterans / Q000276:immunology* / Q000473:pathology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism*; D053661:Interleukin-13 Receptor alpha1 Subunit; D008297:Male; D051379:Mice; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D018123:Receptors, Interleukin / Q000378:metabolism; D053660:Receptors, Interleukin-13; D014132:Trachea / Q000276:immunology / Q000473:pathology* / Q000637:transplantation; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
chemical_list: C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D011506:Proteins; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13