Viral-Driven Mediators of Chronic Lung Allograft Dysfunction

慢性肺同种异体移植功能障碍的病毒驱动介质

• 批准号: 7642267
• 负责人: Richard A Pierce
• 金额: $ 36.9万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-14 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7642267
• 关键词: Allografting; Antibodies; Attenuated; Bone Marrow; Bronchiolitis Obliterans; Bronchoalveolar Lavage; Cells; Cessation of life; Chemotactic Factors; Chronic; Chronic Disease; Chronic lung disease; Cohort Studies; Collagen; Common Cold; Deposition; Development; Disease; Epithelial; Epithelial Cells; Functional disorder; Goals; Homologous Transplantation; Human; Immune; Immune response; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-12; Knowledge; Life; Link; Lung; Lung Transplantation; Lung diseases; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Mouse Strains; Mus; Onset of illness; Patients; Pattern; Phenotype; Proteins; Regression Analysis; Request for Applications; Research; Research Personnel; Respiratory Failure; Risk; Risk Factors; Role; Staging; Syndrome; Therapeutic; Transplant Recipients; Transplantation; Viral; Viral Bronchiolitis; Virus; Virus Diseases; abstracting; airway inflammation; base; cell injury; cohort; cytokine; insight; lung allograft; macrophage; mortality; mouse model; novel; overexpression; pathogen; prevent; programs; prospective; research study; respiratory; response; response to injury

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)

描述（由申请人提供）： 肺移植后的细支气管炎（BO）是一种与发病率和死亡率增加有关的慢性疾病。该疾病导致进行性呼吸衰竭，其特征是气道上皮细胞损伤，气道炎症和气道管腔的纤维闭塞。我们最近证明了先前的呼吸道病毒感染是随后发生死亡和细支性炎症综合征（BOS）的危险因素，即BO的功能表现。我们的长期研究目标是检查气道上皮细胞损伤 - 响应细胞因子在介导病毒依赖性同种异体功能障碍中的作用。对于此应用，我们提出同种异体移植的呼吸道病毒感染会导致上皮细胞损伤增强和上皮损伤 - 反应细胞因子的表达增加。反过来，这些损伤反应细胞因子引发了最终导致同种异体功能障碍的炎症级联反应。为了研究该建议，我们检查了呼吸道病毒感染在小鼠移植模型中的作用。呼吸道病毒感染与移植结合，导致同种异体功能障碍表现为夸张的上皮损伤，巨噬细胞 - 主要的炎症和同种异体移植的纤维闭塞。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-12 p80（p80）的表达增强，这是一种巨噬细胞趋化剂。使用增强或阻断p80功能确认p80的小鼠菌株的其他实验是同种异体移植功能障碍的中心效应。总的来说，这些结果表明p80的表达也可能介导人类的同种异体移植功能障碍。为了支持这种可能性，气道炎症过多的移植受者是随后BOS的已知危险因素，证明p80的支气管肺泡灌洗水平升高，与同种异体移植物中的巨噬细胞积累相关。因此，该提案的目的是确定p80在病毒依赖性同种异体移植功能障碍中的影响，确定p80在病毒依赖性同种异体移植功能障碍中对免疫反应中的作用，并执行对人类肺部移植者的前瞻性群体研究，以表征人类肺部驱动p80 p80表达的人类肺部移植。这些研究将提供有关导致慢性同种异体功能障碍的病毒依赖性病理生理机制的见解，并且可以使用这种知识的剥削来识别旨在防止疾病发作或延迟其进展的治疗策略。 从外行的角度来看，我们以前已经表明，患有肺移植的患者中普通感冒或呼吸道病毒感染与慢性肺部疾病有关。特别是，这些病毒感染增加了慢性肺排斥和死亡的风险。这项研究将研究这些病毒如何引起慢性肺排斥，以便可以开发出这种疾病的治疗方法。 （抽象的结尾）