Lung transplantation is an option for patients with end-stage lung disease. Advances in organ preservation, surgery, and preoperative management have improved outcome. However, despite new modes of immunosuppression, rejection and obliterative bronchiolitis (OB) continue to be barriers to sustained allograft performance. Although histopathology is now the main means of diagnosing acute rejection, safer and more sensitive means of detecting rejection and preclinical OB are needed to test the hypothesis that earlier detection will forestall irreversible impairment. A better understanding of the molecular basis of acute rejection and OB is also needed because it may suggest better therapeutic strategies. Among other potential benefits of such an understanding is identification of surrogate markers of rejection. Lung transplantation studies have been limited by inability to measure potential markers in small samples. Seeking transcriptional signatures of rejection in lung allograft biopsies for diagnostic purposes, we propose using multiplexed, real time PCR amplification of cDNA from endobronchial biopsies (EBB) and transbronchial biopsies (TBB) to profile expression of genes with postulated roles in rejection and remodeling.
Our first aim i s to develop biomarkers for early detection of rejection and OB in EBB and TBB. These studies test the hypothesis that levels of selected gene transcripts in cells from EBB and TBB can constitute a practical gene-based diagnostic test of rejection that is a useful adjunct to standard histopathology while providing fresh insights into the pathogenesis of rejection and obliterative bronchiolitis.
Our second aim i s to explore lavage cell transcripts as proxy biomarkers of rejection-linked inflammation in airway and alveolar walls. To test this hypothesis, we will profile transcripts in lavage cells from allografts to identify products correlating with histopathological rejection in paired EBB and TBB. By comparing profiles of non-transplant controls vs. allograft recipients we will gain insights concerning unique features of transplant-associated lung inflammation. Ultimately, we will test whether protein expression of our candidate genes differs as well in allograft versus control lungs.
Acute and chronic allograft rejection causes much of the morbidity and mortality after lung transplantation. The pathophysiology of rejection is still poorly understood. The development of new approaches for detecting rejection and revelation of new molecular mechanisms may lead to better management and outcomes in lung transplant patients. ? ? ? ?