The Role of Chemokines During Lung Allograft Dysfunction

描述（由申请人提供）：肺移植被认为是终末期肺部疾病患者的一种治疗选择。不幸的是，由于高发病率和严重的肺移植功能障碍，它只是一种治疗，而不是治愈。早期同种异体肺移植功能障碍（缺血再灌注损伤）以中性粒细胞为主的炎症为特征。97%的肺移植受者发生轻度缺血再灌注损伤。更严重的发作死亡率可达40%。重要的是，早期同种异体移植物功能障碍是闭塞性细支气管炎综合征（BOS）发展的重要危险因素。BOS是一种慢性过程，其特征是修复失调和纤维闭塞，在同种异体气道内和周围形成肉芽样组织。BOS是肺移植术后5年生存率仅为42%的主要原因。CXCR2/CXCR2配体生物轴在促进中性粒细胞募集和介导血管生成中起重要作用。我们假设CXCR2/CXCR2配体生物轴对早期->晚期（BOS）同种异体移植物功能障碍的连续性至关重要。为了验证这一假设，我们将使用临床相关的大鼠冷缺血-再灌注损伤模型系统，过渡到临床相关的小鼠气道缺血-再灌注损伤模型，进而发展到小鼠BOS模型。利用这些模型系统，我们将分析CXCR2/CXCR2配体在缺血-再灌注（中性粒细胞募集）和BOS（中性粒细胞非依赖性/血管生成依赖性）期间的双峰生物学功能。然后，我们将对人类标本（即BALF和TBBx）进行探索性转化研究，以证明CXCR2/CXCR2配体生物轴确实有助于早期->晚期同种异体移植物功能障碍的连续性。此外，我们假设早期同种异体移植物功能障碍中存在的CXCR2配体水平升高将预测患者晚期（BOS）同种异体移植物功能障碍的发展。BOS患者BALF中多个CXCR2配体的持续升高将具有显著的血管生成活性，促进BOS发病过程中的纤维闭塞。本研究的目的可能会导致这种生物学和干预的治疗靶点，以减少早期（缺血再灌注损伤）和晚期（BOS）肺移植功能障碍的发生率。

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.