The goal of this proposal is to elucidate physiologic mechanisms that promote gastric aspiration in lung transplant recipients and identify molecular mechanisms by which microaspiration worsens PGD and CLAD. GERD is extremely common in patients with chronic lung disease and lung transplant patients placing them at risk for microaspiration of stomach contents. While investigators recognize microaspiration as a biologically plausible contributor to lung transplant outcomes, data causally linking esophageal dysfunction and GERD-associated microaspiration with graft dysfunction are lacking. Furthermore, whether the lung transplant procedure causes esophageal dysfunction to promote GERD and CLAD is unknown. Given the prevalence of GERD after lung transplant (as high as 75% in some series), some investigators recommend the routine use of fundoplication or universal proton pump inhibitors following lung transplant but that has yielded inconsistent results in ameliorating CLAD while suffering from attendant risks of therapy. We reason that elucidating the physiologic mechanisms driving GERD can at a minimum better stratify patients for surgical therapies like fundoplication. Similarly, understanding the molecular events linking microaspiration with PGD and CLAD can inform the development of medical therapies to treat aspiration-induced injury to prevent or slow CLAD progression. Lung restricted autoantibodies (LRA) against lung self-antigens have emerged among the strongest risk factors for both PGD and CLAD in humans and mice. Multiple studies have shown that over a third of patients undergoing lung transplantation have pre-existing LRA and up to 60-70% of those that are negative initially develop de novo LRA within the first two years of transplantation, which is independently associated with increased CLAD risk. In murine models, LRA drive the pathogenesis of PGD, prevent the development of allotolerance with co- stimulatory blockade, and abrogate established allotolerance. Using a well-established murine model of CLAD developed by a multinational team of investigators, we show exciting new data that acid aspiration results in the de novo development of LRA through recruitment of neutrophils and monocyte derived alveolar macrophages and by promoting antigen epitope spreading. We suggest direct and immunologic injury to the lung epithelium in response to acid aspiration induces mitochondrial dysfunction leading to a pathologic activation of the ISR that precludes epithelial repair. These data support our overarching hypothesis that physiologic dysfunction in the esophagus and accompanying GERD predisposes to the recruitment of neutrophils and MoAM to the allograft resulting in the generation of LRA while to worsen CLAD. We will test this using two interrelated aims: Aim 1: To determine whether acid aspiration recruits neutrophils and monocyte-derived alveolar macrophages to the graft that induce de novo lung-restricted autoantibodies and worsen CLAD. A...