Exposure of human beings to tobacco smoke, as well as to certain dusts and environmental pollutants, incites lung inflammation and in some cases causes cancer. New evidence indicates that chronic inflammation leads to increased susceptibility to lung cancers and to other malignancies. Furthermore, cigarette smoke is the primary cause of chronic obstructive pulmonary disease (COPD-emphysema and chronic bronchitis). Despite the fact that smoking causes lung diseases, remarkably little is known of the mechanisms whereby smoke generates inflammation and how the inflammatory responses are regulated. The fibroblast is a key and numerous cell, not only important for structure, but is also a key orchestrator and amplifier of inflammation. Fibroblasts respond to smoke by increasing their synthesis of proinflammatory mediators such as cyclooxygenase-2 (Cox-2), cytokines and chemokines. Components of cigarette smoke can stimulate cells through the aryl (sometimes called aromatic) hydrocarbon receptor (AhR). Although the AhR is well-known for binding ligands such as the environmental toxicant dioxin and subsequent toxicity, the true physiologic role of the AhR remains unknown. Our new data reveal that genetic deletion of the AhR causes a reduction in the NF(B family member RelB and enhanced lung inflammation (i.e. lung neutrophils, chemokines, Cox-2) in response to smoke. Therefore, presence of the AhR is an unexpected down-regulator of cigarette smoke-induced lung inflammation. Importantly, AhR expression also limits inflammation after LPS exposure, a stimulus that does not signal through the AhR. The overall hypothesis to be tested is that the AhR, via RelB regulation, is an important down-regulator of pulmonary inflammation. Cigarette smoke will be employed as the primary model system. Additional studies using an inflammatory stimulus that does not signal through AhR will also be completed. The following specific aims will test the overall hypothesis:
Aim 1. Determine the effects of AhR deficiency on the inflammatory response to cigarette smoke and IL-12 in primary pulmonary fibroblasts, epithelial cells and macrophages.
Aim 2. Determine whether the AhR regulates the inflammatory response to cigarette smoke in pulmonary fibroblasts (and selected other cell types) by stabilization of the NF(B family member RelB.
Aim 3. Determine the effects of AhR deficiency on cigarette smoke-mediated lung inflammation and emphysema in vivo, and determine the mechanisms involved.
These aims will generate exciting new data to support the role of the AhR as an attenuator of inflammation and will identify key mechanisms involved. This will highlight the AhR as a novel target for therapeutic manipulation in diseases such as COPD. Project Narrative: Lung inflammatory conditions induced by the inhalation of cigarette smoke and other toxicants are the cause of significant morbidity and mortality world-wide. We have identified a previously unknown function for a receptor called the aryl hydrocarbon receptor (AhR) as a "down-regulator" of these harmful inflammatory responses. Our studies will determine the mechanisms by which the AhR acts to dampen lung inflammation. This new knowledge can be exploited to develop new treatments for patients with lung inflammatory diseases.
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