Mechanism of pirfenidone-induced lung transplant survival

吡非尼酮诱导肺移植存活的机制

• 批准号: 7290233
• 负责人: GARY A VISNER
• 金额: $ 8.45万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7290233
• 关键词: Acute; Adverse effects; Affect; Arts; Asthma; Attenuated; Bronchiolitis Obliterans; CD8B1 gene; Cell Adhesion Molecules; Cells; Chronic; Cicatrix; Clinical; Data; Development; Disease; Enzyme-Linked Immunosorbent Assay; Fibrosis; Generations; Hamman-Rich syndrome; Histology; Immune; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Inflammatory; Injury; Intercellular adhesion molecule 1; Interferons; Interleukin-10; Interleukin-12; Interleukin-13; Interleukin-4; Lesion; Long-Term Effects; Lung; Lung Transplantation; Lymphocyte; Lymphocyte Activation; Mediating; Methods; Minor; Modeling; Multiple Sclerosis; Mus; Numbers; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pirfenidone; Production; Property; Quality of life; Rattus; Respiratory physiology; T-Lymphocyte; TNF gene; Testing; Therapeutic Intervention; Therapeutic immunosuppression; Time; Tissues; Toxic effect; Transplantation; Work; cytokine; electric impedance; in vivo; lung allograft; protective effect; response

DESCRIPTION (provided by applicant): Chronic rejection, which remains the most important challenge to the long-term survival and quality of life of lung allograft recipients, is manifested by bronchiolitis obliterans (BO), a fibroproliferative disorder involving the narrowing or obliteration of bronchiolar lumens by scar tissue, with resultant impedance to airflow. Currently, there are no therapeutic interventions, including immunosuppression, that have proven to be of major clinical benefit. Pirfenidone is an anti-fibrotic agent that is effective in blocking the development of fibroproliferative disorders, including clinical idiopathic pulmonary fibrosis. Moreover, this drug is well tolerated clinically, with only minor adverse effects and no significant toxic effects. Although pirfenidone is not known to have immunosuppressive properties, it does alter expression of inflammatory and profibrotic cytokines and alter the incidence of immune-mediated injury in models of multiple sclerosis and asthma. Most importantly, we have found that pirfenidone attenuated chronic airway obstructive lesions in a mouse tracheal transplant model, and reduced both acute cellular rejection and the development of fibrosis in a rat lung transplant model. We now propose to evaluate the mechanisms involved in pirfenidone's graft-protective effects. Our first hypothesis is that pirfenidone reduces transplant-mediated injury and rejection by reducing the production of proinflammatory and profibrotic cytokines and the associated recruitment of host inflammatory cells. We plan to study short- and long-term effects of pirfenidone on lung function and histology. In addition, we will characterize the immune and cytokine response of rat lung allografts receiving pirfenidone treatment, using multi-parameter Luminex and/or ELISA tests to determine BAL and lung levels of Th1 (IFN-?, TNF-?, IL-2, IL-12), Th2 (IL-4, IL-10, IL-13), and Th3 (TGF-¿) cytokines, and expression of the adhesion molecule, ICAM-1. Our second hypothesis is that pirfenidone may also directly block lymphocyte activation and proliferation. This will be evaluated in vitro and in vivo, using state-of-the art methods that will collectively generate a composite and detailed body of work that for the first time will assess direct immune effects of pirfenidone on host CD4 and CD8 T cells. Lastly we believe that pirfenidone has direct effects on the numbers and/or functions of host naturally occurring Foxp3+ Treg cell, thereby contributing to the enhanced survival of rat lung allografts. We will therefore evaluate the effects of pirfenidone on the generation and suppressive activities of host Treg cells in vitro and in vivo. Long term survival for lung transplantation is relatively poor since acute and chronic rejection occurs in the majority of patients. Our preliminary data identified that pirfenidone has protective effects against both acute and chronic rejection in a rat model of lung transplantation. This proposal will further evaluate its potential in promoting long term survival of lung transplants and the mechanisms of its protective effects.

描述（由适用提供）：慢性拒绝仍然是对肺同种异体肺炎接受者的长期生存和生活质量的最重要挑战，它是由支气管炎闭塞剂（BO）表现出来的，玻璃纤维炎（BO）是一种纤维增生性疾病，涉及纤维增生性疾病，涉及稀缺组织的纤维化或消除，并具有导致的压力。目前，没有治疗性干预措施，包括免疫抑制，这些干预措施已被证明具有主要的临床益处。 Pirfenidone是一种抗纤维化剂，可有效阻止纤维增生性疾病的发展，包括临床特发性肺纤维化。此外，这种药物在临床上的耐受性很好，仅较小的不良反应，没有明显的毒性作用。尽管吉富烯酮尚未具有免疫抑制特性，但它确实改变了炎症和纤维化细胞因子的表达，并改变了多发性硬化症和哮喘模型中免疫介导的损伤的入口。最重要的是，我们发现吡非酮减弱了小鼠气管移植模型中的慢性气道阻塞性病变，并减少了急性细胞排斥和大鼠肺移植模型中纤维化的发展。现在，我们建议评估吡非酮的移植物保护作用所涉及的机制。我们的第一个假设是，Pirfenidone通过减少促炎和纤维化细胞因子的产生以及相关的宿主炎症细胞的募集来减少移植介导的损伤和排斥。我们计划研究吡非酮对肺功能和组织学的短期和长期影响。此外，我们将使用多参数Luminex和/或ELISA测试来表征接受Pirfenidone治疗的大鼠肺同种异体移植物的免疫和细胞因子反应，以确定Th1的BAL和肺水平（IFN-？,, tnf-？,, iil-2，il-2，il-2，il-12），th2（il-4，th2（il-4，il-4，il-4，il-4，il-il-10，cy），以及th33333 33-3 33-33-33-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3-3（th 33） - 粘合分子的表达，ICAM-1。我们的第二个假设是，吡非酮也可能直接阻断淋巴细胞的激活和增殖。这将在体外和体内进行评估，使用最先进的方法，该方法将共同生成复合且详细的工作体系，这将首次评估Pirfenidone对宿主CD4和CD8 T细胞的直接免疫作用。最后，我们认为吡非酮对天然发生的Foxp3+ Treg细胞的数量和/或功能有直接影响，从而有助于增强大鼠肺同种异体移植物的生存。因此，我们将评估吡啶酮对体外和体内宿主Treg细胞的产生和抑制活性的影响。肺移植的长期存活相对较差，因为大多数患者发生急性和慢性排斥。我们的初步数据确定，在肺移植大鼠模型中，吡啶酮对急性和慢性排斥具有保护作用。该建议将进一步评估其在促进肺移植物的长期存活及其受保护作用机制方面的潜力。