Abstract
Background
Manifestations of cystic fibrosis, although well-characterized in the proximal airways,
are understudied in the distal lung. Characterization of the cystic fibrosis lung
‘matrisome’ (matrix proteome) has not been previously described, and could help identify
biomarkers and inform therapeutic strategies.
Methods
We performed liquid chromatography-mass spectrometry, gene ontology analysis, and
multi-modal imaging, including histology, immunofluorescence, and electron microscopy
for a comprehensive evaluation of distal human lung extracellular matrix (matrix)
structure and composition in end-stage cystic fibrosis.
Results
Quantitative proteomic profiling identified sixty-eight (68) matrix constituents with
significantly altered expression in end-stage cystic fibrosis. Over 90% of significantly
different matrix peptides detected, including structural and basement membrane proteins,
were expressed at lower levels in cystic fibrosis. However, the total abundance of
matrix in cystic fibrosis lungs was not significantly different from control lungs,
suggesting that cystic fibrosis leads to loss of diversity among lung matrix proteins
rather than an absolute loss of matrix. Visualization of distal lung matrix via immunofluorescence
and electron microscopy revealed pathological remodeling of distal lung tissue architecture
and loss of alveolar basement membrane, consistent with significantly altered pathways
identified by gene ontology analysis.
Conclusions
Dysregulation of matrix organization and aberrant wound healing pathways are associated
with loss of matrix protein diversity and obliteration of distal lung tissue structure
in end-stage cystic fibrosis. While many therapeutics aim to functionally restore
defective cystic fibrosis transmembrane conductance regulator (CFTR), drugs that target
dysregulated matrix pathways may serve as adjunct interventions to support lung recovery.
Key words
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Article info
Publication history
Published online: May 05, 2022
Accepted:
April 20,
2022
Received in revised form:
March 14,
2022
Received:
November 1,
2021
Identification
Copyright
© 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
