Searching for biomarkers for diagnosis and early detection of lung transplant chronic rejection

Lung transplantation has become the established therapy for end-stage lung diseases such as cystic fibrosis, chronic obstructive pulmonary disease (COPD), and others, but the long-term survival rate remains low. The five-year survival rate is only about 50%, which is mainly due to chronic rejection. Chronic rejection is clinically manifested as bronchiolitis obliterans syndrome (BOS), which is characterized as inflammation and fibrosis of the small airways. Chronic rejection is currently diagnosed by measuring the decrease in lung function, but it is practically irreversible after chronic rejection becomes clinically apparent.; The ability to detect chronic rejection in its early stage has been elusive. While acute rejection, CMV (cytomegavirus) pneumonitis, CMV infection, and lymphocytic bronchiolitis have been considered as risk factors for chronic rejection, their ability to act as predictors for the onset of chronic rejection remains unclear. Reliable and accurate biomarkers for the early detection of chronic rejection remain under investigation, however.; One of the most important tools available in this investigation is mass spectrometry (MS), which has been widely used in proteomics research and biomarker study. In this thesis, mass spectrometry was used as a basic research technique for protein identification and quantification to find reliable biomarkers for the diagnosis and early detection of chronic rejection. The peak intensity ratio of clara cell protein to lysozyme demonstrated specificity of 94% and sensitivity of 74% for diagnosis of chronic rejection. A total of 265 proteins were identified using iTRAQ and the diagnostic power of IgM, proteinase 3, and matrix-metalloproteinase 9 were validated using ELISA. Due to the complexity of mass spectrometry data, comprehensive statistical methods will be used to identify protein patterns for the diagnosis and prognosis of chronic rejection. A new statistical method will be discussed in this thesis and, applied to protein data obtained from BALF for the early prediction of chronic rejection. The identification of proteins related to the chronic rejection of lung transplants may provide some important insights into the mechanism of the disease.