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

Aim 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 the fibrotic response and inflammation signals in serum of BOS patients. Methods LTx patients transplanted at the University Medical Center Groningen between 2004 and 2017 were screened. Nineteen patients with BOS were selected and matched to 19 non-BOS patients. 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 BOS and non-BOS patients at any timepoint. OPG was significantly higher in non-BOS compared to BOS six 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 three months before BOS onset in BOS compared to non-BOS patients. C-reactive protein (FDR<0.05) and SERPINA3 (FDR<0.05) amongst others, were higher in end-stage BOS compared to non-BOS patients. Conclusion Differences in expression of proteins that reflect the complex interplay between fibrosis 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.