A Potential Novel Molecular Interaction in Bronchiolitis Obliterans Syndrome in Lung Transplantation Patients: The Role of SERPINA3 and Osteoprotegerin.

Abstract

Chronic lung allograft dysfunction significantly limits survival after lung transplantation. The obstructive phenotype bronchiolitis obliterans syndrome (BOS) is characterized by the abnormal activation of airways epithelium, fibrotic changes with excessive extracellular matrix deposition, and airway obliteration. Mast cells, through mediators such as tryptase and chymase, play a role in lung fibrosis. The proteins osteoprotegerin (OPG) and SERPIN family member A 3 (SERPINA3) have been associated with lung fibrosis progression. Tryptase-mast cells can produce OPG, while chymase interacts with SERPINA3. This study aimed to investigate if and how SERPINA3, OPG, and tryptase/chymase-positive mast cells are related to fibrotic airway obliteration and potentially show an association with BOS severity. Serum SERPINA3 levels in BOS and non-BOS were examined using ELISA. In BOS lung tissue, non-cartilaginous airways were classified into normal, partially obstructed, and completely obstructed airways. Immunohistochemistry detected SERPINA3, OPG, chymase, and tryptase. Colocalization of and interactions between SERPINA3, OPG, and tryptase were assessed by immunofluorescence, proximity ligation assay, and AlphaFold modeling. SERPINA3 serum levels in BOS patients were higher compared to non-BOS patients. A low percentage of SERPINA3 and OPG was detected in partially and completely obstructed airways. Cells positive for OPG and SERPINA3 colocalized with tryptase-mast cells in airways. OPG colocalized with SERPINA3, and they positively correlated in partially obstructed airways. In completely obstructed airways, OPG, SERPINA3, and tryptase all positively correlated with each other. These findings suggest mast cells express SERPINA3 and OPG, and these proteins potentially form a complex in lung tissue, possibly contributing to airway remodeling in BOS.