Viral-Driven Mediators of Chronic Lung Allograft Dysfunction

描述(由申请人提供)： 肺移植后闭塞性细支气管炎(BO)是一种与发病率和死亡率增加相关的慢性疾病。该病导致进行性呼吸衰竭，以呼吸道上皮细胞损伤、呼吸道炎症和气道腔纤维性闭塞为特征。我们最近证明，先前的呼吸道病毒感染是随后发生死亡和闭塞性毛细支气管炎综合征(BOS)的一个明显的危险因素，BOS是BO的功能性表现。我们的长期研究目标是检测呼吸道上皮细胞损伤反应细胞因子在介导病毒依赖的同种异体移植物功能障碍中的作用。对于这一应用，我们认为呼吸道病毒感染同种异体移植物会导致上皮细胞损伤加剧和上皮损伤反应细胞因子的表达增加。反过来，这些损伤反应细胞因子启动炎症级联反应，最终导致同种异体移植物功能障碍。为了研究这一建议，我们研究了呼吸道病毒感染在小鼠移植模型中的作用。呼吸道病毒感染合并移植导致移植物功能障碍，表现为移植物上皮损伤加重、巨噬细胞占优势的炎症和纤维闭塞。接下来，我们证明了病毒感染和移植导致上皮细胞损伤反应细胞因子IL-12p80(P80)表达的协同增加，IL-12p80是一种巨噬细胞趋化物质。使用增强或阻断p80功能的小鼠品系的进一步实验证实，p80是同种异体移植物功能障碍的中心效应器。总体而言，这些结果表明p80的表达也可能介导人类同种异体移植功能障碍。为了支持这种可能性，患有过度呼吸道炎症的移植受者表现出较高的p80支气管肺泡灌洗水平，这与同种异体移植物中巨噬细胞的聚集有关。因此，这项建议的目的是确定p80在病毒依赖的同种异体移植功能障碍中的作用，确定p80在病毒依赖的同种异体移植功能障碍中的免疫反应中的作用，并对人类肺移植受者进行前瞻性队列研究，以表征病毒驱动的p80表达在BOS中的作用。这些研究将深入了解导致慢性同种异体移植物功能障碍的病毒依赖的病理生理机制，并利用这些知识来确定旨在预防疾病发生或延缓其进展的治疗策略。 在外行方面，我们之前已经表明，普通感冒或呼吸道病毒感染与接受肺移植的人的慢性肺部疾病有关。特别是，这些病毒感染增加了慢性肺排斥反应和死亡的风险。这项研究将研究这些病毒是如何导致慢性肺排斥反应的，以便开发这种情况的治疗方法。(摘要结束)

DESCRIPTION (provided by applicant): Bronchiolitis obliterans (BO) following lung transplantation is a chronic disease associated with increased morbidity and mortality. The disease results in progressive respiratory failure and is characterized by airway epithelial cell injury, airway inflammation and fibrous obliteration of the airway lumen. We have recently demonstrated antecedent respiratory viral infection is a distinct risk factor for the subsequent development of death and bronchiolitis obliterans syndrome (BOS), the functional manifestation of BO. Our long-term research objective is to examine the role of airway epithelial cell injury-response cytokines in mediating viral-dependent allograft dysfunction. For this application, we propose respiratory viral infection of the allograft results in enhanced epithelial cell injury and increased expression of epithelial injury-response cytokines. In turn, these injury-response cytokines initiate inflammatory cascades that culminate in allograft dysfunction. To investigate this proposal, we examined the role of respiratory viral infection in a mouse transplant model. Respiratory viral infection in combination with transplantation resulted in allograft dysfunction manifested as exaggerated epithelial injury, macrophage- predominant inflammation and fibrous obliteration of the allograft. We next demonstrated viral infection and transplantation resulted in a synergistic increase in the expression of the epithelial cell injury-response cytokine IL-12 p80 (p80), a macrophage chemoattractant. Additional experiments using mouse strains that enhanced or blocked p80 function confirmed p80 was a central effector of allograft dysfunction. Collectively, these results suggested expression of p80 may also mediate allograft dysfunction in humans. In support of this possibility, transplant recipients with excessive airway inflammation, a known risk factor for subsequent BOS, demonstrated elevated bronchoalveolar lavage levels of p80 that correlated with increased macrophage accumulation in the allograft. Accordingly, the aims of this proposal are to determine the effects of p80 in viral-dependent allograft dysfunction, determine the role of p80 on the immune response in viral-dependent allograft dysfunction, and perform a prospective cohort study of human lung transplant recipients to characterize the role for viral-driven p80 expression in BOS. These studies will provide insight into the viral-dependent pathophysiologic mechanisms that result in chronic allograft dysfunction, and exploitation of this knowledge may be used to identify therapeutic strategies aimed to prevent disease onset or delay its progression. In lay terms, we have previously shown that the common cold, or a respiratory viral infection, is associated with chronic lung disease in people that have had a lung transplant. In particular, these viral infections increase the risk of chronic lung rejection and death. This research will study how these viruses cause chronic lung rejection so that treatments for this condition can be developed. (End of Abstract)