title: Local origin of mesenchymal cells in a murine orthotopic lung transplantation model of bronchiolitis obliterans.
abstract: Bronchiolitis obliterans is the leading cause of chronic graft failure and long-term mortality in lung transplant recipients. Here, we used a novel murine model to characterize allograft fibrogenesis within a whole-lung microenvironment. Unilateral left lung transplantation was performed in mice across varying degrees of major histocompatibility complex mismatch combinations. B6D2F1/J (a cross between C57BL/6J and DBA/2J) (Haplotype H2b/d) lungs transplanted into DBA/2J (H2d) recipients were identified to show histopathology for bronchiolitis obliterans in all allogeneic grafts. Time course analysis showed an evolution from immune cell infiltration of the bronchioles and vessels at day 14, consistent with acute rejection and lymphocytic bronchitis, to subepithelial and intraluminal fibrotic lesions of bronchiolitis obliterans by day 28. Allografts at day 28 showed a significantly higher hydroxyproline content than the isografts (33.21 ± 1.89 versus 22.36 ± 2.33 μg/mL). At day 40 the hydroxyproline content had increased further (48.91 ± 7.09 μg/mL). Flow cytometric analysis was used to investigate the origin of mesenchymal cells in fibrotic allografts. Collagen I-positive cells (89.43% ± 6.53%) in day 28 allografts were H2Db positive, showing their donor origin. This novel murine model shows consistent and reproducible allograft fibrogenesis in the context of single-lung transplantation and represents a major step forward in investigating mechanisms of chronic graft failure.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mimura
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan.
authors.forename: Natalie
authors.initials: N
authors.lastname: Walker
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan.
authors.forename: Casey M
authors.initials: CM
authors.lastname: Manning
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Murdock
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan.
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Myers
authors.affiliation: Department of Pathology, University of Michigan Health System, Ann Arbor, Michigan.
authors.forename: Amir
authors.initials: A
authors.lastname: Lagstein
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan.
authors.forename: John J
authors.initials: JJ
authors.lastname: Osterholzer
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan. Electronic address: vlama@umich.edu.
authors.forename: Vibha N
authors.initials: VN
authors.lastname: Lama
mesh_terms: D000818:Animals; D001989:Bronchiolitis Obliterans / Q000209:etiology / Q000276:immunology / Q000473:pathology*; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology*; D008168:Lung / Q000276:immunology / Q000473:pathology*; D016040:Lung Transplantation / Q000009:adverse effects*; D008214:Lymphocytes / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000276:immunology / Q000473:pathology*; D051379:Mice
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