The ultimate goal of this study is to define pharmacological interventions that impact the inflammatory state in the cigarette smoke exposed lung. The immune response in the lung is composed of tissue-specific responses often to environmental agents that require the coordinated response by multiple immune and non-immune cells. When this becomes dysregulated, then pathologies related to excessive pro-inflammatory responses or fibrosis can result. The VA patient population is particularly at risk because of the disproportionate number of individuals who use cigarettes. In the lung a major target of nicotine is the nicotinic acetylcholine receptor (nAChR) alpha7 (?. This receptor has an exceptionally high permeability to calcium that alone can modulate intracellular signaling pathways regulating of transcription factors, cytokines and chemokines. This project will use newly developed mouse models designed specifically to study the ?inflammatory interaction with cigarette smoke (CS) in the mouse lung and will focus on identification of specific cellular signaling mechanisms controlling this response in alveolar and interstitial macrophages, as well as non-hematopoietic cells of the lung. The overall proposal hypothesis is: Modulation of the nicotinic ?calcium current modifies tissue-specific intracellular signaling pathways in the lung in response to cigarette smoke. We will test this hypothesis in 3 Specific Aims:
In Aim 1 the hypothesis is: Susceptibility to lung damage and compartmentalized inflammatory control is determined by cell-specific ?expression. The preliminary data reveal that alveolar macrophages (AMs), granulocytes, and interstitial cells (hematopoietic and non-hematopoietic) express ? and the expression level in individual animals corresponds to the magnitude of the inflammatory response. The results will for the first time allow us to define how CSand the nicotine in CS, acts through ?to govern the inflammatory response by cells as they transition from a normal to a pro-inflammatory environment.
In Aim 2 the hypothesis is: Calcium signaling through the ?receptor activates cell signaling pathways that control the magnitude of the pro-inflammatory response. Newly developed mouse models that specifically restrict ?calcium channel permeability will be used to define transcriptional and proteomic impacts of this restricted signaling on the nicotine:CS inflammatory response. Finally in Aim3 the hypothesis tested is: The ?calcium mediated signaling pathway(s) contribute to expression of M-CSF and GM-CSF by both lung macrophages and alveolar epithelial cells. We have already found evidence of perturbation of the CSF-signaling system controlled by the ?calcium signaling pathway. We will build upon this preliminary finding and apply our new findings to test the use of potential therapeutic interventions to manipulate the cellular responses dysregulated by CS and the nicotine: ?nteraction to restore a more normal response. At the conclusion of this project we will offer novel insights into the mechanisms controlling the impact of CS on the lung and how the susceptibility to subsequent pathologies may be approached to impact upon this important VA patient issue.
The Veteran patient population disproportionately uses more nicotine containing products, such as cigarettes, which results in altering normal inflammatory lung processes that ultimately lead to pulmonary diseases. One component of cigarette smoke is nicotine which is responsible for addiction through its activation of nicotinic receptors in the brain. However, peripheral tissues also express nicotinic receptors and nicotine activation of these receptors is reported to inhibit inflammation. We are investigating how cigarette smoke and nicotine impact inflammatory responses and how individual variability in expression of nicotinic receptors can predispose an individual to more or less severe lung pathology.
