Oxylipin Mediators Prevent Smoke-Induced Lung Inflammation
Abstracts
Initial Award Abstract |
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It has been well established that cigarette smoke causes squamous cell metaplasia (SCM) in humans and is accompanied by chronic inflammation and a sustained increase in inflammatory cells that can continue, even in former smokers. A possible pathway of transformations that the bronchial epithelium undergoes during chronic inflammation starts by initial hyperplasia through a proliferative transitory state followed by a final stage of squamous metaplasia or atrophy. Based on previous results, we have supporting data that oxylipin mediators of arachidonic acid, epoxyeicosatrienoic acid (EETs) play a major role in the attenuation of acute inflammatory response induced by tobacco smoke. In the proposed study, we extend our knowledge toward a chronic model, where our working hypothesis is that increasing levels of EETs will reduce chronic inflammatory response, lung dysfunction and injury. Since tobacco smoke exposure affects both cardio-pulmonary systems, we propose to use the spontaneously hypertensive (SH) rats as our animal model. SH rats are highly sensitive to tobacco smoke exposure with induction of both pulmonary inflammation and intra-pulmonary airway squamous cell metaplasia associated with chronic obstructive pulmonary disease. Under the proposed objectives we first examine the efficacy of EETs in chronic inflammatory model induced by tobacco smoke, followed by measuring endogenous levels of oxylipin and examining the cardio-pulmonary pathological endpoints associated with these exposure conditions. Mechanism of action involving EETs and pro-inflammatory gene expression will be examined in Objective 3. Our main hypothesis is that activation of PPAR-y by EETs prevents activation of NFkB and hence inhibits pro-inflammatory gene expression, as was shown previously in endothelial cells. We will explore correlations to cells infiltration, blood pressure, proliferation and apoptosis along with pathological events, all with chronic exposure to tobacco smoke and oxylipin mediators. Based on the success of the proposed research a new therapeutic approach to treat chronic pulmonary inflammation will be proposed. |
