title: Persistence of pulmonary pathology and abnormal lung function in IL-3/GM-CSF/IL-5 beta c receptor-deficient mice despite correction of alveolar proteinosis after BMT.
abstract: Mice deficient for the IL-3/GM-CSF/IL-5 beta c receptor (beta cR KO) develop lung disease similar to that seen in human pulmonary alveolar proteinosis (PAP) which includes lymphocytic infiltration around airways and vessels and the progressive accumulation of surfactant and macrophages within the alveolar space. We investigated bone marrow transplantation (BMT) as a curative treatment of PAP in beta cR KO mice by semiquantitative histologic analysis and evaluation of pulmonary function. BMT from wild-type (WT) donors into lethally irradiated beta cR KO recipients (WT --> KO) led to the complete resolution of alveolar protein accumulation and to normalization of BAL fluid cellularity and macrophage morphology. However, detailed microscopic analysis of lung tissue revealed the persistence of significant cellular infiltrates in WT --> KO recipients which were equivalent to those seen in KO --> KO animals. Evaluation of pulmonary function demonstrated that only dynamic compliance (Cdyn) and not airway conductance (G[L]) was significantly improved in the WT --> KO group compared to KO --> KO animals and that both of these measurements remained significantly abnormal when compared to WT --> WT controls. We conclude, that although BMT for PAP reverses alveolar macrophage and protein accumulation, it does not decrease the interstitial inflammatory component of this disease. The importance of this residual pathology is demonstrated by the incomplete correction of alveolar function (Cdyn) and lack of improvement in increased airway resistance (G[L]). These findings may have important implications with regard to the extent that BMT can be considered a potential curative procedure for this clinical disorder.
authors.affiliation: Division of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital, Boston, MA 02115, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Cooke
authors.forename: R
authors.initials: R
authors.lastname: Nishinakamura
authors.forename: T R
authors.initials: TR
authors.lastname: Martin
authors.forename: L
authors.initials: L
authors.lastname: Kobzik
authors.forename: J
authors.initials: J
authors.lastname: Brewer
authors.forename: J A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: D
authors.initials: D
authors.lastname: Bungard
authors.forename: R
authors.initials: R
authors.lastname: Murray
authors.forename: J L
authors.initials: JL
authors.lastname: Ferrara
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D006801:Humans; D008168:Lung / Q000473:pathology*; D008170:Lung Compliance; D051379:Mice; D018345:Mice, Knockout; D011649:Pulmonary Alveolar Proteinosis / Q000473:pathology* / Q000628:therapy; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency*; D018123:Receptors, Interleukin / Q000172:deficiency*; D016185:Receptors, Interleukin-3 / Q000172:deficiency*; D053649:Receptors, Interleukin-5
chemical_list: D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D018123:Receptors, Interleukin; D016185:Receptors, Interleukin-3; D053649:Receptors, Interleukin-5