Integrated Mechanisms of Primary and Chronic Graft Dysfunction Following Lung Transplantation

Lung transplantation is increasingly used to treat an expanding list of end-stage lung diseases, resulting in a more than 50% increase in the number of lung transplant procedures in the United States in the past decade. Unfortunately, survival following lung transplantation is the worst among solid organ transplants, with only 80% and 50% of patients alive after 1 and 5 years, respectively. Acute and chronic rejection, known as primary graft dysfunction (PGD) and chronic lung allograft rejection (CLAD), respectively, are the major drivers of these poor outcomes.

In this this PPG award, investigators led by SQLIFTS Translational Innovation Program Director Ankit Bharat, MD seek to identify common mechanisms that cause PGD and CLAD in mouse models and in patients, with a goal of identifying new treatments that will improve survival for lung transplant recipients. PGD affects over 50% of recipients within 24 hours of transplantation and has emerged as the most important risk factor for both short-term mortality and long-term graft loss from CLAD. The investigators in this PPG have made important contributions to a growing molecular understanding of the complex interplay between immune and lung parenchymal cells that underlie PGD and CLAD.

In Project 1, led by Ankit Bharat, MD, we dissect molecular mechanisms underlying our discovery that lung restricted alloantibodies (LRA), present in over 30% of lung transplant recipients, are associated with PGD. In Project 2, led by Harris Perlman, PhD, we dissect physiologic and molecular mechanisms underlying prevalent abnormalities in esophageal function that lead to acid aspiration and worsen CLAD severity. In Project 3, led by SQLIFTS Technology Program Director Alexander Misharin, MD, PhD, we credential profibrotic monocyte-derived alveolar macrophages (MoAM) as causal drivers of lung fibrosis in murine models and in patients with CLAD. In Project 4, led by Early Stage Investigator SeungHye Han, MD, we test whether mitochondrial dysfunction in the alveolar epithelium predisposes lung transplant recipients to pathologic activation of the integrated stress response (ISR) that precludes lung repair. 

Together our published and preliminary data support our overarching hypothesis that acute neutrophil-mediated lung injury mechanisms such as PGD and acid aspiration drive CLAD progression by promoting the development of LRA, recruiting profibrotic MoAM, and inducing epithelial cell mitochondrial damage causing an ISR-mediated barrier to epithelial repair. Our work will identify actionable pathways that can be therapeutically targeted to improve lung transplant outcomes. This multidisciplinary program is strongly rooted in the Northwestern Medicine Lung Transplant Program, which is known for clinical innovation in developing lung transplant as a salvage therapy for COVID-19 and lung cancer and which in 2024 performed the highest number of lung transplants in the United States.