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Published ahead of print on June 15, 2007, doi:10.1164/rccm.200702-335OC

Am. J. Respir. Crit. Care Med., Volume 176, Number 7, October 2007, 713-723

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Submitted on February 27, 2007
Accepted on June 14, 2007

A New Murine Model for Obliterative Bronchiolitis Post-Bone Marrow Transplant

Angela Panoskaltsis-Mortari1*, Kevin V Tram2, Andrew P Price2, Christine Wendt3, and Bruce R Blazar2

1 Department of Pediatrics, Division of Hematology/Oncology, Blood and Marrow Transplant Program, Cancer Center, University of Minnesota, Minneapolis, MN, USA; Division of Pulmonary, Allergy and Critical Care Medicine, University of Minnesota, Minneapolis, MN, USA, 2 Department of Pediatrics, Division of Hematology/Oncology, Blood and Marrow Transplant Program, Cancer Center, University of Minnesota, Minneapolis, MN, USA, 3 Division of Pulmonary, Allergy and Critical Care Medicine, University of Minnesota, Minneapolis, MN, USA

* To whom correspondence should be addressed. E-mail: panos001{at}umn.edu.

Rationale: Obliterative bronchiolitis (OB) is a major problem in lung transplantation and is also part of the spectrum of late onset pulmonary complications that can occur after hematopoietic stem cell transplant (HSCT). Better mouse models are needed to study the onset of this disease so that therapeutic interventions can be developed. Objectives: Our goal was to develop an OB mouse model. Methods: Recipients were lethally conditioned and given a rescue dose of T cell-depleted, allogeneic BM supplemented with a sublethal dose of allogeneic T cells. Main Results: At 2 months post-BMT, the lungs had extensive perivascular and peribronchiolar inflammation consisting of CD4+ T cells, CD8+ T cells, B cells, macrophages, neutrophils and fibroblasts. In contrast to the acute model, histology showed airway obstruction consistent with OB. Epithelial cells of airways in the early stages of occlusion exhibited changes in expression of cytokeratins. Whereas the lung had severe allogeneic BMT-mediated disease, there was only mild to moderate graft-vs-host disease in liver, colon, skin and spleen. High wet/dry weight ratios and elevated hydroxyproline were seen, consistent with pulmonary edema and fibrosis. Mice with OB exhibited high airway resistance and low compliance. Increases in many inflammatory mediators in the lungs of mice that develop OB were seen early post transplant and not later at the time of OB. Conclusion: This new mouse model will be useful for the study of OB associated with late post-HSCT onset and chronic GVHD, and that also leads to poor outcome in the lung transplant setting.


Key words: obliterative bronchiolitis, mouse models, transplantation







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