The Role of Chemokines During Lung Allograft Dysfunction

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DESCRIPTION (provided by applicant): Lung transplantation is considered to be a therapeutic option for patients with end-stage lung diseases. Unfortunately, due to the high incidence and severity of lung allograft dysfunction it is only a treatment and not a cure. Early lung allograft dysfunction (ischemia-reperfusion injury) is characterized by a neutrophil predominated inflammation. Mild ischemia-reperfusion injury occurs in up to 97% of lung transplantation recipients. The mortality rate for more severe episodes can be >40%. Importantly, early allograft dysfunction is a significant risk factor for the development of bronchiolitis obliterans syndrome (BOS). BOS is a chronic process with features of dysregulated repair and fibro-obliteration with granulation-like tissue formation within and around allograft airways. BOS is the main reason that the 5-year survival after lung transplantation is only 42%. The CXCR2/CXCR2 ligand biological axis is important in promoting neutrophil recruitment and in mediating angiogenesis. We hypothesized that CXCR2/CXCR2 ligand biological axis is critical to the continuum of early -> late (BOS) allograft dysfunction. To test this hypothesis, we will use a rat model system of clinically relevant cold ischemia-reperfusion injury, transition to a murine model of clinically relevant airway ischemia-reperfusion injury, which progresses to a murine model of BOS. Using these model systems we will dissect the bimodal biological function of CXCR2/CXCR2 ligands during ischemia-reperfusion (recruitment of neutrophils) and BOS (neutrophil-independent/angiogenesis-dependent). We will then perform exploratory translational studies on human specimens (i.e., BALF and TBBx) to demonstrate that the CXCR2/CXCR2 ligand biological axis indeed contributes to the continuum of early -> late allograft dysfunction. Moreover, we postulate that elevated levels of CXCR2 ligands present in early allograft dysfunction will predict the development of late (BOS) allograft dysfunction in patients. The persistent elevations of multiple CXCR2 ligands in BALF from patients with BOS will have significant angiogenic activity promoting fibro-obliteration during the pathogenesis of BOS. The aims in this proposal may lead to therapeutic targets for this biology and intervention to reduce the incidence of early (ischemiareperfusion injury) and late (BOS) lung allograft dysfunction.