Published ahead of print on March 9, 2006, doi:10.1164/rccm.200509-1381OC
Am. J. Respir. Crit. Care Med., Volume 173, Number 11, June 2006, 1276-1282
A more recent version of this article appeared on June 1, 2006
Submitted on September 6, 2005
Accepted on March 8, 2006
Fibroblasts of Recipient Origin Contribute to Bronchiolitis Obliterans in Human Lung Transplants
Verena Brocker1, Florian Langer1, Tariq G Fellous2, Michael Mengel1, Mairi Brittan2, Martin Bredt1, Simone Milde1, Tobias Welte3, Matthias Eder4, Axel Haverich5, Malcolm R Alison2, Hans Kreipe1, and Ulrich Lehmann1*
1 Institute of Pathology, Medizinische Hochschule Hannover, Hannover, Germany,
2 Institute of Cell and Molecular Science, Diabetes and Metabolic Medicine, Queen Mary University of London, London, United Kingdom,
3 Department of Pneumology, Medizinische Hochschule Hannover, Hannover, Germany,
4 Department of Hematology, Hemostaseology and Oncology, Medizinische Hochschule Hannover, Hannover, Germany,
5 Division of Thoracic and Cardiovascular Surgery, Medizinische Hochschule Hannover, Hannover, Germany
* To whom correspondence should be addressed. E-mail: Lehmann.Ulrich{at}MH-Hannover.de.
Rationale: The participation of circulating precursor cells in the development of experimental pulmonary fibrosing lesions in mice has been recently demonstrated.
Objectives: This study analyzes whether circulating, bone marrow-derived fibroblastic precursor cells contribute to the development of fibrosing lesions in human lungs, especially bronchiolitis obliterans.
Methods: The occurrence of in situ-microchimerism in bronchiolitis obliterans lesions of human lung allografts (n = 12) as well as of autologous lung tissue from patients post bone marrow-transplantation (n = 2) was analyzed using laser-assisted microdissection after immunohistochemical labeling of leukocytes followed by STR-PCR-based genotyping. Combined immunofluorescence and fluorescence in situ hybridization for sex chromsomes was performed for independent confirmation in cases with appropriate sex mismatch (n = 2).
Measurements and Main Results: The bronchiolitis obliterans lesions of all twelve lung transplant patients contained considerable numbers of recipient-derived fibroblasts (mean: 32%). The fibrosing pulmonary lesions of the two bone marrow-transplanted patients displayed also clear in situ-microchimerism. The in situ detection methodology confirmed these results, although to a lower degree (6-16%).
Conclusions: These data clearly demonstrate the involvement of circulating fibroblastic precursor cells in the development of human fibrosing lung lesions and provide evidence that these cells are most probably bone marrow-derived. These results may open new venues regarding the prevention of fibrosis in lung transplants and potentially other organs.
Key words: in situ-microchimerism, bone marrow-derived progenitors, lung fibrosis, transplantation
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