Pathological activation of integrated stress response as a driver of Chronic allograft dysfunction after lung transplant

PROJECT SUMMARY Lung transplantation is the only viable therapeutic option to extend and improve the quality of life for many patients with end stage lung disease. However, survival following lung transplantation is the worst among solid organs with only 80% and 50% of patients alive at one and five years, respectively. Primary graft dysfunction (PGD) after lung transplantation, resulting from ischemia reperfusion injury, is the predominant cause of poor lung transplant early outcomes. Chronic lung allograft dysfunction (CLAD) with lung fibrosis is the leading cause of morbidity and late mortality after lung transplant. Epidemiologic data suggest a strong link between PGD and CLAD but the molecular mechanisms underlying this association are unknown. Our laboratory has shown that non-classical monocytes in the donor lung are necessary for neutrophil recruitment to the allograft leading to PGD after lung transplantation. In parallel studies, we showed that activation of the integrated stress response in the alveolar epithelium precludes alveolar epithelial differentiation after injury. Based on these published and preliminary data, we hypothesize that early PGD induces a chronic activation of the integrated stress response in the airway and alveolar epithelium that precludes epithelial differentiation in response to injury, predisposing to a risk of CLAD. We will test this hypothesis in three interrelated specific aims. Aim 1: To determine whether ISR (Integrated Stress Response) mediated activation of ATF4 is necessary for impaired alveolar epithelial repair after lung transplantation. Aim 2: To determine whether ameliorating PGD by targeting donor derived nonclassical monocytes reduces the severity of CLAD. Aim 3: To determine whether activation of the ISR in the airway and alveolar epithelium in lung predisposes patients at an increased risk of early CLAD. We will test our hypotheses in clinically relevant murine models of PGD and CLAD following lung transplantation. We will credential our findings in humans by applying multi-omic technologies to the analysis of samples collected longitudinally after lung transplantation. Our studies are designed to credential targets for therapy that can be administered at the time of transplant to reduce the long term risk of CLAD.