The Role of Chemokines During Lung Allograft Dysfunction

趋化因子在肺同种异体移植功能障碍中的作用

• 批准号: 7842039
• 负责人: JOHN A BELPERIO
• 金额: $ 28.85万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7842039
• 关键词: Allografting; Alveolar; Binding; Biological; Biological Markers; Biological Models; Biological Process; Biology; Brain Death; Bronchiolitis Obliterans; CXC Chemokines; Chemotactic Factors; Chronic; Data; Development; Diffuse; Event; Extravasation; Fiber; Functional disorder; G-Protein-Coupled Receptors; Human; Hypoxemia; IL8 gene; IL8RB gene; Incidence; Inflammation; Injury; Interleukin-8B Receptor; Intervention; Ischemia; Lead; Ligands; Lung; Lung Transplantation; Lung diseases; Mediating; Modeling; Morbidity - disease rate; Mus; Nature; Neutrophil Infiltration; Pathogenesis; Patients; Play; Prevention; Process; Rattus; Reperfusion Injury; Reperfusion Therapy; Risk Factors; Role; Severities; Source; Specimen; Staging; Syndrome; Testing; Therapeutic; Time; Tissues; Transplantation; Vascular remodeling; angiogenesis; base; chemokine; clinically relevant; insight; lung allograft; lung ischemia; mortality; neutrophil; novel; repaired; research study; therapeutic target; translational study

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.

描述（由申请人提供）：肺移植被认为是末期肺部疾病患者的治疗选择。 不幸的是，由于肺同种异体功能障碍的发病率和严重程度高，这只是一种治疗而不是治愈方法。 早期同种异体移植功能障碍（缺血再灌注损伤）的特征是中性粒细胞主要炎症。轻度缺血再灌注损伤发生在多达97％的肺移植受者中。 更严重发作的死亡率> 40％。 重要的是，早期的同种异体功能障碍是开发细支气管炎综合征（BOS）的重要危险因素。 BOS是一个慢性过程，其修复和纤维融合功能失调的特征在同种异体移植气道内部和周围具有肉芽样组织形成。 BOS是肺移植后5年生存率仅为42％的主要原因。 CXCR2/CXCR2配体生物轴对促进中性粒细胞募集和介导血管生成很重要。 我们假设CXCR2/CXCR2配体生物轴对早期 - >晚（BOS）同种异体功能障碍至关重要。 为了检验这一假设，我们将使用临床上相关的冷缺血再灌注损伤的大鼠模型系统，过渡到临床相关气道缺血 - 再灌注损伤的鼠模型，该模型发展为BOS的鼠模型。 使用这些模型系统，我们将在缺血 - 再灌注（嗜中性粒细胞的募集）和BOS（中性粒细胞独立/血管生成依赖性）期间剖析CXCR2/CXCR2配体的双峰生物学功能。 然后，我们将对人类标本（即BALF和TBBX）进行探索性翻译研究，以证明CXCR2/CXCR2配体生物轴确实确实有助于早期 - >晚期同种异体功能障碍。 此外，我们假设早期同种异体移植功能障碍中存在的CXCR2配体水平升高将预测患者晚期（BOS）同种异体功能障碍的发展。 BAS患者BALF中多个CXCR2配体的持续升高将具有显着的血管生成活性，可促进BOS发病机理期间纤维融合。 该提案的目的可能导致该生物学和干预措施的治疗靶标，以减少早期（缺血性灌注损伤）和晚期（BOS）肺同种异体移植功能障碍的发生率。

项目成果

Validation of a method to screen for pulmonary hypertension in advanced idiopathic pulmonary fibrosis.

晚期特发性肺纤维化肺动脉高压筛查方法的验证。

• DOI: 10.1378/chest.07-2488
• 发表时间: 2008
• 期刊: Chest
• 影响因子: 9.6
• 作者: Zisman,DavidA;Karlamangla,ArunS;Kawut,StevenM;Shlobin,OksanaA;Saggar,Rajeev;Ross,DavidJ;Schwarz,MarvinI;Belperio,JohnA;Ardehali,Abbas;Lynch3rd,JosephP;Nathan,StevenD
• 通讯作者: Nathan,StevenD

Pulmonary hypertension associated with lung transplantation obliterative bronchiolitis and vascular remodeling of the allograft.

• DOI: 10.1111/j.1600-6143.2008.02338.x
• 发表时间: 2008-09
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Saggar R;Ross DJ;Saggar R;Zisman DA;Gregson A;Lynch JP 3rd;Keane MP;Weigt SS;Ardehali A;Kubak B;Lai C;Elashoff D;Fishbein MC;Wallace WD;Belperio JA
• 通讯作者: Belperio JA

Protection against bronchiolitis obliterans syndrome is associated with allograft CCR7+ CD45RA- T regulatory cells.

• DOI: 10.1371/journal.pone.0011354
• 发表时间: 2010-06-29
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Gregson AL;Hoji A;Palchevskiy V;Hu S;Weigt SS;Liao E;Derhovanessian A;Saggar R;Song S;Elashoff R;Yang OO;Belperio JA
• 通讯作者: Belperio JA

Serum albumin concentration and waiting list mortality in idiopathic interstitial pneumonia.

特发性间质性肺炎的血清白蛋白浓度和等候名单死亡率。

• DOI: 10.1378/chest.08-0754
• 发表时间: 2009
• 期刊: Chest
• 影响因子: 9.6
• 作者: Zisman,DavidA;Kawut,StevenM;Lederer,DavidJ;Belperio,JohnA;Lynch3rd,JosephP;Schwarz,MarvinI;Tayek,JohnA;Reuben,DavidB;Karlamangla,ArunS
• 通讯作者: Karlamangla,ArunS

Treprostinil to reverse pulmonary hypertension associated with idiopathic pulmonary fibrosis as a bridge to single-lung transplantation.

曲前列环素逆转与特发性肺纤维化相关的肺动脉高压，作为单肺移植的桥梁。

• DOI: 10.1016/j.healun.2009.05.017
• 发表时间: 2009
• 期刊: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
• 作者: Saggar,Rajeev;Shapiro,ShelleyS;Ross,DavidJ;Fishbein,MichaelC;Zisman,DavidA;Lynch3rd,JosephP;Weigt,SamS;Ardehali,Abbas;Belperio,JohnA;Saggar,Rajan
• 通讯作者: Saggar,Rajan