title: Chronic rejection pathology after orthotopic lung transplantation in mice: the development of a murine BOS model and its drawbacks.
abstract: Almost all animal models for chronic rejection (CR) after lung transplantation (LTx) fail to resemble the human situation. It was our attempt to develop a representative model of CR in mice. Orthotopic LTx was performed in allografts receiving daily immunosuppression with steroids and cyclosporine. Controls included isografts and mice only undergoing thoracotomy (SHAM). Allografts were sacrificed 2, 4, 6, 8, 10 or 12 weeks after LTx. Pulmonary function was measured repeatedly in the 12w allografts, isografts and SHAM mice. Histologically, all allografts demonstrated acute rejection (AR) around the blood vessels and airways two weeks after LTx. This decreased to 50-75% up to 10 weeks and was absent after 12 weeks. Obliterative bronchiolitis (OB) lesions were observed in 25-50% of the mice from 4-12 weeks. Isografts and lungs of SHAM mice were normal after 12 weeks. Pulmonary function measurements showed a decline in FEV(0.1), TLC and compliance in the allografts postoperatively (2 weeks) with a slow recovery over time. After this initial decline, lung function of allografts increased more than in isografts and SHAM mice indicating that pulmonary function measurement is not a good tool to diagnose CR in a mouse. We conclude that a true model for CR, with clear OB lesions in about one third of the animals, but without a decline in lung function, is possible. This model is an important step forward in the development of an ideal model for CR which will open new perspectives in unraveling CR pathogenesis and exploring new treatment options.
authors.affiliation: Laboratory of Pneumology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: De Vleeschauwer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jungraithmayr
authors.forename: Shana
authors.initials: S
authors.lastname: Wauters
authors.forename: Stijn
authors.initials: S
authors.lastname: Willems
authors.forename: Manuela
authors.initials: M
authors.lastname: Rinaldi
authors.forename: Annemie
authors.initials: A
authors.lastname: Vaneylen
authors.forename: Stijn
authors.initials: S
authors.lastname: Verleden
authors.forename: Anna
authors.initials: A
authors.lastname: Willems-Widyastuti
authors.forename: Ken
authors.initials: K
authors.lastname: Bracke
authors.forename: Guy
authors.initials: G
authors.lastname: Brusselle
authors.forename: Erik
authors.initials: E
authors.lastname: Verbeken
authors.forename: Dirk
authors.initials: D
authors.lastname: Van Raemdonck
authors.forename: Geert
authors.initials: G
authors.lastname: Verleden
authors.forename: Bart
authors.initials: B
authors.lastname: Vanaudenaerde
mesh_terms: D000818:Animals; D001989:Bronchiolitis Obliterans / Q000473:pathology* / Q000628:therapy*; D002908:Chronic Disease; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000473:pathology*; D006801:Humans; D016040:Lung Transplantation / Q000473:pathology* / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013577:Syndrome; D013997:Time Factors; D014184:Transplantation, Homologous