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

项目总结 众所周知，硫磺芥末会以剂量依赖的方式影响呼吸道，导致时间- 由不同的潜在发病机制引起的肺损伤的相互依存的“阶段”。急性损伤的特点是 呼吸道纤维蛋白管型形成。这一阶段之后是肺部感染，有可能 进展为慢性呼吸道肺纤维化，如闭塞性细支气管炎(BO)和肺实质 纤维化(PF)，发生在幸存者的急性损伤后数月至数年。这种慢性纤维性肺病 据估计，多达50%-75%的SM接触者会发生这种情况，导致严重的迟发- 发病、发病率和死亡率。目前的治疗重点是提供支持性措施，目前尚不清楚 预防、阻止或逆转呼吸道或实质肺纤维化发展的治疗。近期 我们实验室的数据表明，由于气道管型阻塞而导致的急性死亡可以通过 即使在6-24小时后开始使用呼吸道递送的组织纤溶酶原激活剂(TPA) 吸入SM。不幸的是，SM吸入性损伤急性期的幸存者，即使接受了tPA治疗，也可以 在我们的大鼠模型中仍然发展为亚急性肺部感染和随后的慢性肺纤维化， 极大地增加了潜在的发病率和死亡率。最近，我们发现抗纤维化药物吡非尼酮， 吸入丹参10天后开始给药，可减少肺功能异常，减少 SM暴露后促纤维化的转化生长因子-β和血小板衍生生长因子信号与PF和BO相关。在这个项目中， 我们假设抗纤维化药物吡非尼酮和/或九替丹尼可以降低PF和/或BO 病理、生化改变和肺生理功能障碍，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。 开发和靶向抗生素治疗可能有助于减轻肺纤维化。 这些方法应该为SM吸入幸存者的治疗提供有效的治疗方法。来测试他们的 作为潜在的抗纤维化药物，吡非尼酮和奈替丹尼将在10天后立即口服 在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。 他们在这个模型中的功效。这项建议将开发治疗SM后肺纤维化的实用制剂(S) 吸气。

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.