Abstract
Activation of nicotinic acetylcholine receptor alpha7 subunit (α7nAChR) by nicotine leads to the improved survival rate in experimental model of sepsis. Previously, we demonstrated that heme oxygenase (HO)-1 inducers or carbon monoxide significantly increased survival of lipopolysaccharide (LPS)-induced and cecal ligation and puncture-induced septic mice by reduction of high mobility group box 1 release, a late mediator of sepsis. However, that activation of α7nAChR by nicotine provides anti-inflammatory action through HO-1 upregulation has not been elucidated. Here we show that HO-1-inducible effect by nicotine was mediated through sequential event-Ca(2+) influx, classical protein kinase C activation, and reactive oxygen species production-which activates phosphoinositol-3-kinase/Akt/Nrf-2 pathway. In addition, HO-1 is required for nicotine-mediated suppression of tumor necrosis factor-α, inducible nitric oxide synthase, and high mobility group box 1 expression induced by LPS in macrophages, as evidenced by the fact that nicotine failed to inhibit production of these mediators when HO-1 was suppressed. Importantly, nicotine-induced survival rate was reduced by inhibition of HO-1 in LPS- and cecal ligation and puncture-treated septic mice. Collectively, these data suggest that activation of α7nAChR by nicotine is critical in the regulation of anti-inflammatory process, which could be mediated through HO-1 expression. Thus, we conclude that activation of α7nAChR by nicotine provides anti-inflammatory action through HO-1 upregulation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / pharmacology*
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Calcium Signaling / drug effects
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Cell Line
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Endotoxemia / genetics
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Endotoxemia / metabolism
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Gene Expression Regulation / drug effects
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HMGB1 Protein / metabolism
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Heme Oxygenase-1 / antagonists & inhibitors
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Heme Oxygenase-1 / genetics
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Heme Oxygenase-1 / metabolism*
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Humans
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Inflammation / chemically induced
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Inflammation / prevention & control*
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Kaplan-Meier Estimate
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Lipopolysaccharides / toxicity
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Macrophages / drug effects*
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Macrophages / metabolism
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Male
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Mice
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Mice, Inbred BALB C
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NADPH Oxidases / metabolism
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NF-E2-Related Factor 2 / metabolism
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Nicotine / pharmacology*
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Nicotinic Agonists / pharmacology*
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Nitric Oxide Synthase Type II / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Kinase C / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Reactive Oxygen Species / metabolism
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Receptors, Nicotinic / metabolism*
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Sepsis / genetics
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Sepsis / metabolism*
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Signal Transduction / drug effects
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Tumor Necrosis Factor-alpha / metabolism
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alpha7 Nicotinic Acetylcholine Receptor
Substances
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Anti-Inflammatory Agents
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Chrna7 protein, human
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Chrna7 protein, mouse
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HMGB1 Protein
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Lipopolysaccharides
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NF-E2-Related Factor 2
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Nfe2l2 protein, mouse
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Nicotinic Agonists
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Reactive Oxygen Species
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Receptors, Nicotinic
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Tumor Necrosis Factor-alpha
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alpha7 Nicotinic Acetylcholine Receptor
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Nicotine
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Heme Oxygenase-1
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NADPH Oxidases
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Protein Kinase C