Alpha-7 Nicotinic Acetylcholine Receptor Regulation of NF-kB and Nerve Growth Factor Expression Resulting in Airway Hyperresponsiveness
Introduction. The dangers of tobacco smoke are well known in today’s world.1, 2, 3 Cigarette smoking has many adverse effects, some including, airway hyperresponsiveness, altered tissue structure, and more.1 Airway hyperresponsiveness (AHR) is the constriction of airway smooth muscle cells and is a hallmark of asthma.1, 4 Understanding the mechanisms by which AHR occurs can help better the therapies used in controlling asthma.1, 4 The proposed mechanism suggests that the nicotine component of tobacco stimulates nerve growth factor (NGF) through a NFkB and alpha-7 nicotinic acetylcholine receptor (a7 nAChR) dependent mechanism.1 NGF has been found to increase substance P nerve fiber density, which contributes to AHR.3 Methods. Lung fibroblasts from wild type (WT) and a7 nAChR deficient mice were treated with nicotine.1 ELISA was used to measure levels of NGF.1 The downstream nicotine-induced effects of NFkB on NGF were measured through NFkB nuclear translocation, si-p65 NFkB knockdown, and chromatin immunoprecipitation assays (ChIP).1 NGF expression was measured using RT2 ProfilerTM PCR Array.3 Substance P nerve fiber density was measured using a Zeiss LSM 510 confocal microscope.3 Results. Of the wild type mice and mice deficient in a7 nAChR, levels of nerve growth factor were found to be elevated in WT mice exposed to nicotine.1 WT mice showed significant elevated nuclear translocation of p65.1 Inhibition of NFkB with competitive antagonist negated the induction of NGF.1 ChIP confirmed the binding of NFkB components to the NGF promoter.1 Expression of NGF expression was found to be elevated in mice given side-stream tobacco smoke treatment compared to mice given filtered-air treatment.3 Treatment of NGF antibodies diminished the side-stream tobacco smoke-enhanced substance P innervation.3 Conclusions. Nicotine has been found to stimulate nerve growth factor through the a7 nAChR and NFkB dependent pathways.1 Educating individuals on smoking cessation and limiting nicotine intake remains a vital tool as a form of treatment.5 Targeting NGF with antibodies could potentially be used as another form of treatment for AHR or other lung conditions.6 The findings of this mechanism render nicotine-replacement therapy as impractical.
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