Novel therapies for cigarette smoke induced lung injury

描述(申请人提供)：香烟烟雾是一种严重的炎症刺激，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、癌症和慢性阻塞性肺病(慢性支气管炎和肺气肿)。吸烟的影响在戒烟后很长一段时间内仍然存在，在肺气肿的情况下，甚至可能继续恶化。这表明香烟烟雾会干扰正常的消炎过程。以前人们认为炎症的消退是一个被动的过程；现在知道消解是一个由特定的促消解脂质介质(PRM)管理的主动过程。这些介质包括脂氧素、溶血素、保护素和乳脂素，它们通过抑制促炎信号和炎细胞迁移，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而发挥作用。其中一种化合物已经在治疗炎症性眼病的临床试验中。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定的抗炎和促分解作用，并能抑制急性香烟烟雾诱导的炎症和小鼠模型中的肺泡扩张。我们的总体假设是，促分解脂类介质对急性和慢性肺损伤都有深刻的抗炎和促化解作用，用促分解类介质治疗促进分解是治疗吸烟引起的炎症性疾病的一个新的重要目标。为了研究这一假设，我们提出了以下具体目标。具体目的1.利用原代人肺细胞和香烟烟雾诱导的小鼠急性肺炎症模型，在体内外确定最有效的促进急性炎症消退的PRM，并确定其作用机制。具体目的2.测定吸烟所致慢性肺病患者肺组织中PRM谱的变化，评价PRM在慢性烟雾暴露小鼠模型中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，促分解介质可用于预防炎症，加速因急性和慢性香烟烟雾暴露而造成的肺损伤的缓解/修复。我们的结果将为这些令人兴奋的新化合物的翻译开发铺平道路，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.