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.
Resolution of inflammation, a natural process in which inflamed or injured tissue returns to normal health, is impaired by cigarette smoking. This project will investigate the utility of a new class of pro-resolving molecules in preventing and treating lung inflammation and injury due to smoking. These compounds have great potential as new human therapies for smoking-related lung disease.
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|Lacy, Shannon H; Woeller, Collynn F; Thatcher, Thomas H et al. (2016) Human lung fibroblasts produce proresolving peroxisome proliferator-activated receptor-? ligands in a cyclooxygenase-2-dependent manner. Am J Physiol Lung Cell Mol Physiol 311:L855-L867|
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