Anti-fibrotic therapies for chronic lung disease due to sulfur mustard

硫芥引起的慢性肺病的抗纤维化治疗

• 批准号: 9145052
• 负责人: Livia Agnes Veress
• 金额: $ 88.39万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9145052
• 关键词: Acute; Affect; Alteplase; Antibiotic Therapy; Antibiotics; Antidotes; Biochemical; Breathing; Bronchiolitis Obliterans; Cessation of life; Chronic; Chronic Phase; Chronic lung disease; Data; Development; Dose; Drug Delivery Systems; Drug Kinetics; Employment; Epithelial; Evaluation; Exposure to; Fibrin; Fibrosis; Functional disorder; Gases; Goals; Hour; Human; Individual; Infection; Inflammation; Inhalation Exposure; Injury; Laboratories; Laboratory Rat; Lead; Lung; Lung diseases; Measures; Modeling; Morbidity - disease rate; Mustard Gas; Obstruction; Oral; Organism; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Permeability; Pharmaceutical Preparations; Phase; Physiological; Pirfenidone; Platelet-Derived Growth Factor; Play; Pulmonary Fibrosis; Pulmonary function tests; Rattus; Respiratory System; Respiratory tract structure; Role; Route; Signal Transduction; Survivors; Testing; Time; Transforming Growth Factor beta; Treatment Protocols; Vesicants; airway obstruction; attenuation; effective therapy; improved; lung injury; mortality; prevent; pulmonary function; standard of care; therapy development

PROJECT SUMMARY Sulfur mustard is well known to affect the respiratory tract in a dose-dependent fashion, resulting in time- dependent `phases' of lung injury caused by differing underlying pathogenesis. The hallmark of acute injury is airway fibrin cast formation. This phase is followed by infection within the pulmonary tract, with the potential for progression to chronic pulmonary fibrosis of airways, as in bronchiolitis obliterans (BO) and lung parenchymal fibrosis (PF), occurring months to years after acute injury in survivors. Such chronic fibrotic lung disease conditions are estimated to occur in as many as 50-75% of SM exposed individuals, causing significant late- onset morbidity and mortality. Current treatment focuses on providing supportive measures, with no known therapy to prevent, stop progression of, or revere airway or parenchymal lung fibrosis development. Recent data in our laboratory has indicated that acute mortality due to airway cast obstruction can be eliminated with the employment of airway-delivered tissue plasminogen activator (tPA), even when started 6-24 hours after SM inhalation. Unfortunately, survivors of the acute phase of SM inhalation injury, even if treated with tPA, can still develop subacute pulmonary infections and subsequent chronic lung fibrosis in our rat model, contributing significantly to latent morbidity and mortality. More recently, we found that the anti-fibrotic drug pirfenidone, when started 10 days after SM inhalation, decreased pulmonary function abnormalities and diminished the elevated pro-fibrotic TGF-β and PDGF signaling associated with PF and BO after SM exposure. In this project, we hypothesize that the anti-fibrotic drugs pirfenidone and/or nintedanib will decrease PF and/or BO pathology, biochemical changes, and lung physiologic dysfunction, including gas exchange and lung function tests. Additionally, we hypothesize that infection may play a key role in lung fibrosis development, and treatment with targeted antibiotics may be beneficial in alleviation of lung fibrosis. These approaches should provide effective therapies for treatment of SM inhalation survivors. To test their potential as anti-fibrotic agents, pirfenidone and nintedanib will be given orally immediately after or 10 days after SM exposure. We will also evaluate possible underlying mechanisms by which the therapies may exert their efficacy in this model. This proposal will develop practical agent(s) for treatment of lung fibrosis after SM inhalation.

项目摘要 众所周知，硫芥以剂量依赖性方式影响呼吸道，导致时间- 由不同的潜在发病机制引起的肺损伤的依赖性“阶段”。急性损伤的特征是 气道纤维蛋白管型形成。这一阶段之后是肺部感染，有可能 进展为气道慢性肺纤维化，如闭塞性细支气管炎（BO）和肺实质 纤维化（PF），发生在幸存者急性损伤后数月至数年。这种慢性纤维化肺病 据估计，多达50-75%的SM暴露个体会出现这种情况，导致严重的晚期- 发病率和死亡率。目前的治疗重点是提供支持性措施， 预防、阻止气道或实质肺纤维化发展或逆转气道或实质肺纤维化发展的治疗。最近 我们实验室的数据表明， 使用气道递送的组织纤溶酶原激活剂（tPA），即使在6-24小时后开始 SM吸入剂。不幸的是，SM吸入性损伤急性期的幸存者，即使用tPA治疗， 在我们的大鼠模型中仍然发生亚急性肺部感染和随后的慢性肺纤维化， 对潜在发病率和死亡率有显著影响。最近，我们发现抗纤维化药物吡非尼酮， 吸入SM后10天开始，肺功能异常减少， SM暴露后与PF和BO相关的促纤维化TGF-β和PDGF信号传导升高。在这个项目中， 我们假设抗纤维化药物吡非尼酮和/或尼达尼布将降低PF和/或BO 病理学、生化变化和肺生理功能障碍，包括气体交换和肺 功能测试此外，我们假设感染可能在肺纤维化中起关键作用 因此，使用靶向抗生素进行治疗可能有益于减轻肺纤维化。 这些方法应该为SM吸入幸存者的治疗提供有效的疗法。测试他们 吡非尼酮和尼达尼布可能作为抗纤维化药物，将在给药后立即或10天内口服给药 SM暴露后。我们还将评估这些疗法可能发挥作用的潜在机制。 在这个模型中的功效。该建议将开发用于治疗SM后肺纤维化的实用药物 吸入。