Survival after lung transplantation is limited to a median of 5-year due to development of bronchiolitis obliterans syndrome (BOS). BOS is the clinical manifestation of chronic allograft dysfunction, characterised by inflammation and fibrosis of small/medium-sized airways leading to airflow obstruction. Numerous insults to the transplanted lungs have been associated with BOS development. Alarmins are cell derived danger signals released from damaged tissue which activate innate and adaptive immune responses. We hypothesised that the release of alarmins into the airway compartment after lung transplantation may contribute to BOS pathogenesis.Methods
A retrospective longitudinal study of 52 lung transplant recipients from 2005 to present was performed (26 recipients developed BOS; 26 remained free from BOS). All recipients had lung function and bronchoalveolar lavage (BAL) performed at 1, 3, 6 and 12 months post transplant. Further samples were taken if the diagnostic criteria for BOS were fulfilled. A total of 214 BAL samples were analysed by ELISA for the alarmins Interleukin-1a (IL-1a) and High Motility Group-Box1 (HMG-B1). Data were analysed using Mann–Whitney tests.Results
Both BOS and non-BOS recipients with culture positive BAL samples had significantly higher concentrations of IL-1a and HMG-B1 than culture negative samples. Due to the confounding effect of infection, our analysis excluded 90 BAL samples with positive cultures. Concentrations of IL-1a were significantly higher in culture negative BAL from BOS patients (median 2.411, range [AJF1] 0.073–19.078 pg/ml) than from Non-BOS patients (median 1.424, range [AJF2] 1.159–17.41 pg/ml; p=0.001). No significant difference in HMG-B1 concentrations between the two groups was observed (BOS median 58.906, range 0–197.5; Non-BOS median 76.25, range 0–211.563 ng/ml; p=0.2378). Longitudinal measurements of IL-1a in BOS patients showed significantly higher levels 3 months before or after BOS diagnosis (median 3.935, range 1.122–13.544 pg/ml), compared to >3 months before BOS diagnosis (median 2.015, range 0.073–14.669 pg/ml; p=0.0153). There was no such difference in HMG-B1 concentrations (p=0.9164).Conclusions
An increase in the alarmin IL-1a, but not HMG-B1, is associated with BOS development. The cellular source of IL-1a requires further evaluation but may be a marker of airway epithelial injury and/or play a mechanistic role in BOS development via its secretion by other cell types.