Abstract
Bronchiolitis obliterans syndrome, a common form of chronic lung allograft dysfunction, is the major limitation to long-term survival after lung transplantation. The histologic correlate is progressive, fibrotic occlusion of small airways, obliterative bronchiolitis lesions, which ultimately lead to organ failure. The molecular composition of these lesions is unknown. In this sutdy, the protein composition of the lesions in explanted lungs from four end-stage bronchiolitis obliterans syndrome patients was analyzed using laser-capture microdissection and optimized sample preparation protocols for mass spectrometry. Immunohistochemistry and immunofluorescence were used to determine the spatial distribution of commonly identified proteins on the tissue level, and protein signatures for 14 obliterative bronchiolitis lesions were established. A set of 39 proteins, identified in >75% of lesions, included distinct structural proteins (collagen types IV and VI) and cellular components (actins, vimentin, and tryptase). Each respective lesion exhibited a unique composition of proteins (on average, n = 66 proteins), thereby mirroring the morphologic variation of the lesions. Antibody-based staining confirmed these mass spectrometry-based findings. The 14 analyzed obliterative bronchiolitis lesions showed variations in their protein content, but also common features. This study provides molecular and morphologic insights into the development of chronic rejection after lung transplantation. The protein patterns in the lesions were correlated to pathways of extracellular matrix organization, tissue development, and wound healing processes.
Highlights
Bronchiolitis obliterans syndrome, a common form of chronic lung allograft dysfunction, is the major limitation to long-term survival after lung transplantation
This study shows a link between the morphologic appearance of obliterative bronchiolitis (OB) lesions in remodeled airways in lungs from patients experiencing end-stage bronchiolitis obliterans syndrome (BOS) and their respective protein content
These findings corroborate results from earlier studies from our group obtained in a larger patient cohort, where early extracellular matrix changes were shown to be associated with later development of BOS.[29]
Summary
Bronchiolitis obliterans syndrome, a common form of chronic lung allograft dysfunction, is the major limitation to long-term survival after lung transplantation. The histologic correlate is progressive, fibrotic occlusion of small airways, obliterative bronchiolitis lesions, which lead to organ failure. The molecular composition of these lesions is unknown In this sutdy, the protein composition of the lesions in explanted lungs from four end-stage bronchiolitis obliterans syndrome patients was analyzed using laser-capture microdissection and optimized sample preparation protocols for mass spectrometry. This study provides molecular and morphologic insights into the development of chronic rejection after lung transplantation. Since the first lung transplantations in the late 1980s, bronchiolitis obliterans syndrome (BOS) in the form of progressive airway obstruction has been recognized as the most important pathology associated with adverse outcome. The pathologic correlate to BOS was identified as Supported by the Swedish Medical Research Council 2016-01190 (G.W.-T.), the Evy and Gunnar Sandberg Foundation 2015 (G.W.-T.), the Swedish Heart-Lung Foundation 20190297 (G.W.-T.), the Alfred Österlund Foundation 20191209 (G.W.-T.), the Royal Physiographic Society in Lund 20191114 (G.W.-T.), the Swedish Foundation for Strategic Research SBE13-0130 (G.W.-T.), ALF 2018 Project0097 Government Public Health grant (G.W.-T.), and the Inga and John Hains Foundation 20170906 (C.M.)
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