Quercetin (3,3',4',5,7-pentahydroxyflavone) is the major flavonoid in the human diet. It is found in onions, broccoli, apples, berries and tea, and present in extracts from Ginko biloba and St. John's Wort, both popular health supplements. Flavonoids share a common chemical structure consisting of two phenol rings linked through three carbons. Quercetin has potent antioxidant effects, combining with free radical species to form considerably less reactive phenoxy radicals. Quercetin also has inhibitory effects on several lipid, protein tyrosine and serine/threonine kinases, including phosphatidylinositol (PI) 3-kinase. Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation with goblet cell hyperplasia, irreversible airway obstruction, chronic bacterial infection of the lower airways, reduced mucociliary clearance, emphysema;and impaired innate immunity. Flavonoids with antioxidant and anti-inflammatory properties may influence chronic inflammatory diseases such as COPD. Dietary intake of flavonols (a subclass of flavonoids including quercetin and kaempferol) has been positively associated with pulmonary function (FEV1) and inversely associated with chronic cough and breathlessness in Dutch COPD patients (6). Further, intake of polyphenol-containing fruit was inversely correlated with 20-yr COPD mortality in three European countries (7). Together these studies suggest that quercetin and other flavanoids may positively influence outcome in COPD. We have shown that quercetin, administered by gavage needle, blocks airways hyper-responsiveness and monocyte chemoattractant protein (MCP-1/CCL2) expression in a mouse model of asthma by attenuating signaling through a PI 3-kinase/Akt/nuclear factor (NF)-?B pathway. In the latter study, quercetin also increased airway epithelial cell eukaryotic initiation factor (eIF)-2? phosphorylation, a key event in the antiviral response which limits viral protein synthesis and replication. In addition, results from our pilot studies suggest that quercetin inhibits interleukin (IL)-8/CXCL8 expression from airway epithelial cells and human monocyte- derived macrophages in response to P. aeruginosa infection. Quercetin also decreased invasion of epithelial cells by P. aeruginosa. Quercetin reduced lung inflammation and loss of elastic recoil in lipopolysaccharide (LPS) and elastase-treated mice with physiologic and histologic changes typical of COPD, as well as the inflammatory response of these "COPD" mice to non-typeable H. influenzae. Finally, quercetin inhibited internalization of rhinovirus (RV) in cultured airway epithelial cells and reduced RV-induced neutrophilic inflammation in vivo. Based on these observations, we offer the general hypothesis that quercetin modulates innate immune responses in COPD. To test this hypothesis, we propose the following Specific Aims. Specific Aim 1: Determine the effects of quercetin on airway inflammation and tissue destruction in a mouse model of COPD. We hypothesize that: 1) quercetin attenuates airways inflammation and emphysematous changes caused by elastase and LPS, a constituent of cigarette smoke;2) quercetin reduces LPS-induced inflammatory responses in alveolar macrophages by inhibiting recruitment of CD14, extracellular signal regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinase to lipid rafts;3) reduction of LPS-induced tumor necrosis factor (TNF)-1 expression, in turn, attenuates epithelial cell expression of C-X-C chemokines and mucin glycoproteins;and 4) quercetin prevents LPS-induced oxidative stress in macrophages and airway epithelial cells. Specific Aim 2: Determine the effects of quercetin on the innate response to bacterial infection in a mouse model of COPD. We hypothesize that: 1) after infection with H. influenzae or P. aeruginosa, quercetin inhibits lung inflammation in LPS and elastase-treated "COPD mice;" 2) quercetin inhibits Toll-like receptor (TLR)-mediated pro-inflammatory responses in airway epithelial cells;3) quercetin attenuates PI 3-kinase- dependent bacterial uptake in airway epithelial cells;and 4) quercetin reduces cytotoxic effects by inhibiting bacteria-induced oxidative stress in epithelial cells. Specific Aim 3: Determine the effects of quercetin on the innate response to rhinoviral infection in a mouse model of COPD. We have developed an animal model of RV infection using RV1B, a minor group RV which binds to the low-density lipoprotein receptor (LDL-R). We hypothesize that: 1) quercetin inhibits neutrophilic airway inflammation in RV-infected LPS- and elastase-treated "COPD mice;" 2) quercetin inhibits internalization of RV in airway epithelial cells;3) quercetin decreases airway epithelial cell C-X-C chemokine expression;and 4) quercetin increases the expression of interferon (IFN)-3 in mononuclear cells and increases the phosphorylation of eukaryotic initiation factor (eIF)-a1 in airway epithelial cells, thereby reducing viral load. Understanding the basic mechanisms by which quercetin modulates inflammation in a mouse model of COPD may lead to a new treatment for this devastating disease. PUBLIC HEALTH REVELANCE: Chronic obstructive pulmonary disease (COPD) is increasingly common cause of disability and death in the U.S. There are few effective treatments for this disease. This proposal examines the effects of quercetin, a plant derivative with antioxidant and anti-inflammatory actions, on the innate immune response in a mouse model of COPD. We will examine the effects of quercetin on the pathogenesis of COPD, as well as exacerbations of COPD caused by bacterial and viral infections. Underlying cellular and biochemical mechanisms will also be examined. This proposal may lead to a new nutraceutical treatment for COPD.
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