Novel therapies for cigarette smoke induced lung injury

描述（申请人提供）：吸烟是一种深刻的炎症刺激，吸烟引起的慢性炎症会导致多种致命疾病，包括心血管疾病、癌症和COPD（慢性支气管炎和肺气肿）。吸烟的影响在戒烟后仍会持续很长时间，在肺气肿的情况下甚至会继续恶化。这表明香烟烟雾干扰了正常的消炎过程。以前人们认为炎症的消退是一个被动的过程；现在知道，溶解是一个由特定的促溶解脂质介质（PRMs）管理的主动过程。这些介质，包括脂毒素、溶解蛋白、保护蛋白和蛋白，通过抑制促炎信号传导和炎症细胞迁移，促进促炎效应功能，如巨噬细胞吞噬凋亡的炎症细胞和碎片。其中一种化合物已经用于炎症性眼病的临床试验。我们有强有力的初步数据表明，一种名为resolvin D1 （RvD1）的PRM对人类肺细胞具有特异性的抗炎和促溶解作用，并且可以抑制小鼠模型中香烟引起的急性炎症和空域扩大。我们的总体假设是，促溶性脂质介质对急性和慢性肺损伤都具有深远的抗炎和促溶作用，用促溶性介质促进肺损伤的消退是吸烟引起的炎症性疾病的一个新的重要治疗目标。为了研究这一假设，我们提出了以下具体目标。具体目标确定在体外和体内促进急性炎症消退最有效的PRMs，并通过原代人肺细胞和香烟引起的急性肺部炎症小鼠模型确定其作用机制。具体目标2。确定烟雾引起的慢性肺部疾病的人类样本中PRM谱的变化，并在慢性烟雾暴露小鼠模型中评估PRM预防和治疗肺组织破坏的能力和机制。这些研究将首次表明，促溶解介质可用于预防炎症和加速急性和慢性香烟烟雾暴露引起的肺损伤的消退/修复。我们的研究结果将为这些令人兴奋的新化合物的转化开发铺平道路，这些化合物有可能成为有史以来第一个有效治疗人类慢性炎症和吸烟疾病的药物。

DESCRIPTION (provided by applicant): Cigarette smoke is a profound inflammatory stimulus and the chronic inflammation caused by cigarette smoking contributes to multiple fatal diseases including cardiovascular disease, cancer, and COPD (chronic bronchitis and emphysema). The effects of smoking persist long after smoking cessation, and in the case of emphysema can even continue to worsen. This suggests that cigarette smoke interferes with the normal processes that resolve inflammation. It was previously believed that resolution of inflammation was a passive process; it is now known that resolution is an active process managed by specific pro-resolving lipid mediators (PRMs). These mediators, including lipoxins, resolvins, protectins and maresins, act by inhibiting pro-inflammatory signaling and inflammatory cell migration and promoting pro-resolving effector functions such as macrophage phagocytosis of apoptotic inflammatory cells and debris. One of these compounds is already in clinical trials for inflammatory eye disease. We have strong preliminary data that a PRM called resolvin D1 (RvD1), has specific anti-inflammatory and pro-resolving effects on human lung cells, and can inhibit acute cigarette smoke-induced inflammation and airspace enlargement in a mouse model. Our overall hypothesis is that pro-resolving lipid mediators will have profound anti-inflammatory and pro-resolving effects on both acute and chronic lung injury, and that treatment with pro-resolving mediators to promote resolution is a novel and important therapeutic goal for inflammatory diseases caused by cigarette smoking. To investigate this hypothesis we have proposed the following specific aims. Specific Aim 1. Determine PRMs with the greatest efficacy at promoting resolution of acute inflammation in vitro and in vivo and determine their mechanism of action using primary human lung cells and a mouse model of cigarette smoke-induced acute lung inflammation. Specific Aim 2. Determine changes in the PRM profile of human samples with smoke-induced chronic lung disease, and evaluate the ability and mechanism by which PRMs prevent and treat lung tissue destruction in a mouse model of chronic smoke exposure. These studies will show for the first time that pro-resolving mediators can be used to prevent inflammation and accelerate resolution/repair of lung injury due to both acute and chronic cigarette smoke exposure. Our results will pave the way for translational development of these exciting new compounds that have the potential to be the first ever effective therapies against human diseases of chronic inflammation and smoking.