It takes two: Aberrant repair and low-grade inflammation characterize bronchiolitis obliterans syndrome after lung transplantation in serum proteomic analysis

Abstract

Background

The obstructive phenotype of chronic lung allograft dysfunction, bronchiolitis obliterans syndrome (BOS), is diagnosed after lung transplantation (LTx) when irreversible airway obstruction is already present. This study aimed to investigate biomarkers indicative of aberrant repair resulting in a fibrotic response and inflammation signals in the serum of patients with BOS.

Methods

LTx patients transplanted at the University Medical Center Groningen between 2004 and 2017 were screened. Nineteen patients with BOS were selected and matched with 19 patients with non-BOS. Only patients for whom lung function and longitudinal serum samples post-LTx were available were included. Enzyme-linked immunosorbent assays were performed for neoepitopes of collagen types I, III, and VI and osteoprotegerin (OPG) in serum. Additionally, serum samples were analyzed by label-free liquid chromatography with tandem mass spectrometry proteomics analysis.

Results

Collagen neoepitopes did not differ significantly between patients with BOS and non-BOS at any timepoint. OPG was significantly higher in non-BOS compared to BOS 6 months before BOS onset (p < 0.04). In proteomics analysis, proteins indicating cell repair and proliferation, namely human type II keratin-6 and centromere protein F (both FDR < 0.1), were significantly lower 3 months before BOS onset in patients with BOS compared to patients with non-BOS. C-reactive protein (FDR < 0.05) and SERPINA3 (FDR < 0.05), among others, were higher in end-stage patients with BOS compared to patients with non-BOS.

Conclusions

Differences in the expression of proteins that reflect the complex interplay between aberrant repair and inflammation in BOS were identified. These proteins should be investigated and validated in larger cohorts and may aid in expanding knowledge about the development of BOS.