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The effect of quercetin on human neutrophil elastase-induced mucin5AC expression in human airway epithelial cells

Division of Respiratory Medicine, Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
International immunopharmacology (Impact Factor: 2.47). 07/2012; 14(2):195-201. DOI: 10.1016/j.intimp.2012.07.008
Source: PubMed

ABSTRACT

Quercetin, a plant flavonoid, is a potent antioxidant and anti-inflammatory agent. Mucus hypersecretion is a common pathological change in chronic inflammatory diseases of the airway. We investigated the effect of quercetin on mucin 5AC (MUC5AC) expression induced by human neutrophil elastase (HNE) in airway epithelial cells and its molecular mechanisms. Human airway epithelial (HBE16) cells were pretreated with quercetin and were treated with HNE. We found that HNE induced a significant increase in the levels of MUC5AC and EGFR in cells treated only with HNE. Quercetin suppressed gene transcription and protein expression of MUC5AC in a dose-dependent manner, with significant inhibition from 40 μM. mRNA and protein expressions of EGFR decreased markedly when pretreated with quercetin. Among three MAPK proteins, only phosphorylated ERK1/2 protein expression increased significantly after treatment with HNE alone and decreased significantly after pretreatment with quercetin. HNE also activated phosphorylated PKC protein expression which was attenuated when pretreated with quercetin. These results suggest that quercetin can inhibit HNE-induced MUC5AC expression in human airway epithelial cells through PKC/EGFR/ERK signal transduction pathway. In the future, quercetin might be a valuable treatment for mucin hypersecretion in chronic inflammatory airway diseases in clinic.

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    • "Besides its direct elastolytic activity, NE releases soluble epidermal growth factor receptor (EGFR) ligands and initiates EGFR/MEK/ERK signaling [7]. Furthermore, NE's actions activate the Toll-like receptor 4 (TLR-4)/ MyD88/TRAF6/NF-κB or/and PKC/EGFR/ERK signal transduction pathways and lead to IL-8/CXCL8 release and mucin5AC expression in epithelial cells [8] [9]. In animal models, genetic deficiency or pharmacological intervention with small-molecule or physiological inhibitors of NE affords significant protection (i.e. a reduction of approximately 60%) against the pro-inflammatory and emphysematous effects of chronic exposure to cigarette smoke [10] [11]. "
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    ABSTRACT: Neutrophil chemotaxis is involved in the lung inflammatory process in conditions such as chronic obstructive pulmonary disease (COPD). Neutrophil elastase (NE), one of the main proteases produced by neutrophils, has an important role in the inflammatory process via the release of chemokines from airway epithelial cells. It was recently shown that roflumilast N-oxide has therapeutic potential in COPD. The aim of the present study was to investigate roflumilast N-oxide's effect on NE-induced chemokine production and signaling pathways in A549 epithelial cells. A549 cells were incubated with NE for 30min, washed with PBS and then cultured for 2h (for measurement of mRNA expression) and 24h (for chemokine release) or for 5 to 30min (for protein phosphorylation assays). Prior to the addition of NE, cells were also pre-incubated with prostaglandin E2 (PGE2), alone and in combination with roflumilast N-oxide. Addition of NE was associated with elevated chemokine production by A549 cells and induction of the p38α pathway. In contrast when combined with PGE2, the roflumilast N-oxide had an additive effect on the inhibition of NE-induced chemokine release and p38α and other kinases activation. In conclusion, we demonstrated that NE is able to increase the release of chemokines from epithelial cells via the activation of p38α MAP-kinase and that roflumilast N-oxide when combined with PGE2 lowers NE-induced kinase activation and chemokine production.
    Full-text · Article · Jan 2016 · International immunopharmacology
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    • "Several studies have also revealed its anti-inflammatory potential in airway pathologies that are usually associated with mucus hypersecretion. Using airway epithelial cells (HBE16), quercetin treatment was shown to reduce neutrophil elastase induced MUC5AC expression both at RNA and protein level through PKC/EGFR/ERK signal transduction pathway [130]. In addition, quercetin also attenuated IL-1b-induced MUC5AC expression by modulating ERK and p38 MAPK phosphorylation [131]. "
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    ABSTRACT: Deregulated mucin expression is a hallmark of several inflammatory and malignant pathologies. Emerging evidence suggests that, apart from biomarkers, these deregulated mucins are functional contributors to pathogenesis in inflammation and cancer. Both overexpression and downregulation of mucins in various organ systems is associated with pathobiology of inflammation and cancer. Restoration of mucin homeostasis has become an important goal for therapy and management of such disorders and has fueled the quest for selective mucomodulators. With improved understanding of mucin regulation and mechanistic insights into their pathobiological roles, there is optimism to find selective non-toxic agents capable of modulating mucin expression and function. Recently, natural compounds derived from dietary sources have drawn attention due to their anti-inflammatory and anti-oxidant properties and low toxicity. Considerable efforts have been directed towards evaluating dietary natural products as chemopreventive and therapeutic agents; identification, characterization and synthesis of their active compounds; and improving their delivery and bioavailability. We describe the current understanding of mucin regulation, rationale for targeting mucins with natural products and discuss some natural products that modulate mucin expression and functions. We further discuss the approaches and parameters that should guide future research to identify and evaluate selective natural mucomodulators for therapy.
    Full-text · Article · Jan 2015 · Cancer Treatment Reviews
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    • "All of these effects are beneficial for the prevention and treatment of pulmonary diseases. Theaflavins, exocarpium citri grandis, Forsythia, breviscapine, naringenin, farrerol and quercetin are typical clinically used flavonoids and flavonoid-containing therapeutic agents (55–57). Due to their low costs and high availability from natural sources, these medicines have great potential for development as medicines for chronic inflammatory airway diseases. "
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    ABSTRACT: Airway mucus hypersecretion is a significant clinical and pathological feature of chronic inflammatory airway diseases. Its clinical presentations include recurrent coughing and phlegm. Airway mucus is closely associated with the occurrence, development and prognosis of chronic inflammatory airway diseases and critically affects the lung function, quality of life, hospitalization rate and mortality of patients with chronic inflammatory airway diseases. Therefore, expectorant therapies targeting the potential mechanisms of mucus hypersecretion have been the focus of numerous studies. Conventional expectorants are mainly mucoactive medicines, including nausea-stimulating expectorants, mucolytics, mucokinetics, and proteases and nucleases. In addition, certain traditional Chinese herbal medicines and non-mucoactive agents, including muscarinic acetylcholine receptor antagonists, corticosteroids, leukotriene receptor antagonists and macrolide antibiotics, have also shown expectorant effects. Several novel medicines for expectorant therapy have emerged, including cholesterol-lowering statins, epidermal growth factor receptor tyrosine kinase inhibitors, phosphodiesterase-4 inhibitors, stanozolol, surfactants, flavonoids, tachykinin receptor antagonists, protease inhibitors, cytokine antagonists and purinergic agonists. With the increasing number of multidisciplinary studies, the effectiveness of expectorant therapy for the treatment of chronic inflammatory airway diseases has been confirmed. Therefore, the development of novel expectorants and the standardization of expectorant therapy are the direction and focus of future studies, thus benefiting patients who have a chronic inflammatory airway disease.
    Full-text · Article · Apr 2014 · Experimental and therapeutic medicine
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