Lung transplantation is a potentially lifesaving option for patients with end-stage lung diseases, such as idiopathic pulmonary fibrosis (IPF). However, the median survival following lung transplantation is less than six years, limited primarily by chronic lung allograft dysfunction (CLAD). Emerging data suggest that dysfunction of telomeres, the nucleoprotein caps that protect chromosomes during cellular replication, can result in IPF. It is unknown whether telomere dysfunction also plays a role in CLAD. Were that to be the case, the same pathophysiology that necessitated transplant might also underlie its failure. Our preliminary data show that shorter telomeres in peripheral blood of lung allograft donors predict decreased survival in lung allograft recipients. We also have found that telomere dysfunction in airway progenitor cells is sufficient to induce the pathologic hallmarks of CLAD in an experimental murine model. In humans, progenitor cells such as type II alveolar epithelial cells (AEC2) can proliferate and differentiate to restore epithelial integrity following injury. Thus, AEC2 failure, driven by telomere dysfunction, could lead to denuded alveolar epithelium that is replaced by fibrotic tissue. With the support of this award, we will test the innovative hypothesis that telomere dysfunction is a molecular driver of CLAD. In Study Aim 1, we will evaluate the associations between telomere genetic variants and CLAD in a large, established, multi-center cohort of lung transplant recipients. Common genetic variants resulting in short telomeres will be sequenced, and telomere length will be determined by quantitative PCR. We will use adjusted Cox proportional hazards models to evaluate the links between donor telomere length or genotype and CLAD-free survival time. These findings will help distinguish the contributions of innate and acquired telomere dysfunction to poor post-transplant outcomes.
Study Aim 2 will test the association between short allograft AEC2 telomeres and CLAD-free survival in a longitudinal cohort. AEC2 telomere length will be determined by fluorescence-in situ hybridization with a telomere-specific probe (Telo- FISH) on transbronchial biopsy tissues co-labeled with the AEC2 maker, surfactant protein C. We will test the association between AEC2 telomere length within the first 60 days post-transplant and CLAD-free survival using adjusted Cox models.
This aim will directly assess the link between early AEC2 telomere dysfunction and CLAD. In Study Aim 3, we will determine whether transplant-associated lung injury and lymphocytic inflammation are associated with time to CLAD, using a novel murine model of telomere-mediated CLAD pathology. Overall, this proposed investigation has the potential to challenge our conceptual understanding of CLAD and inform cutting edge therapeutic interventions. Establishing telomere dysfunction as a molecular driver of CLAD would be new paradigm, potentially transforming clinical approaches and thus improving outcomes for patients with end-stage lung disease.
Although telomere regions at the ends of human chromosomes normally shorten with age, accelerated shortening can lead to diseases like idiopathic pulmonary fibrosis (IPF) that may necessitate lung transplantation. This proposal tests the innovative hypothesis that accelerated telomere shortening may also cause loss of function in the transplanted lung. This novel paradigm could lead to novel diagnostics and interventions to improve survival following lung transplantation.
