Novel therapies for cigarette smoke induced lung injury

描述（由申请人提供）：香烟烟雾是一种严重的炎症刺激，吸烟引起的慢性炎症可导致多种致命疾病，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持续很长时间，并且在肺气肿的情况下甚至可以继续恶化。这表明香烟烟雾干扰了消除炎症的正常过程。以前认为炎症消退是一个被动过程;现在已知消退是一个由特定促消退脂质介质（PRM）管理的主动过程。这些介质，包括脂氧素、消退素、保护素和maresins，通过抑制促炎信号传导和炎性细胞迁移并促进促消退效应子功能（如凋亡炎性细胞和碎片的巨噬细胞吞噬作用）起作用。其中一种化合物已经在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（RvD 1）的PRM对人类肺细胞具有特异性抗炎和促消退作用，并可以抑制小鼠模型中急性香烟烟雾诱导的炎症和空域扩大。我们的总体假设是，促消退脂质介质对急性和慢性肺损伤都具有深刻的抗炎和促消退作用，并且用促消退介质促进消退的治疗是吸烟引起的炎性疾病的一个新的和重要的治疗目标。为了研究这一假设，我们提出了以下具体目标。 具体目标1。确定在体外和体内促进急性炎症消退方面具有最大功效的PRM，并使用原代人肺细胞和香烟烟雾诱导的急性肺部炎症小鼠模型确定其作用机制。 具体目标2。确定烟雾诱导的慢性肺病患者样本的PRM特征的变化，并评估PRM预防和治疗慢性烟雾暴露小鼠模型肺组织破坏的能力和机制。 这些研究将首次表明，促缓解介质可用于预防炎症并加速急性和慢性香烟烟雾暴露所致肺损伤的缓解/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首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.