Abigail Bourland

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.

1. Wongtrakool C, Grooms K, Bijli KM, Crothers K, Fitzpatrick AM, et al. (2014) Nicotine Stimulates Nerve Growth Factor in Lung Fibroblasts through an NFkB-Dependent Mechanism. PLoS ONE 9(10): e109602. doi:10.1371/journal.pone.0109602
2. Huang LW, Sun G, Wang DL, Kong LF. ​Inhibition of nerve growth factor/tyrosine kinase receptor A signaling ameliorates airway remodeling in chronic allergic airway inflammation.​ Eur Rev Med Pharmacol Sci. 2015 Jun;19(12):2261-8. PubMed PMID: 26166652.
3. Wu ZX, Hunter DD, Batchelor TP, Dey RD. ​Side-stream tobacco smoke-induced airway hyperresponsiveness in early postnatal period is involved nerve growth factor.​ Respir Physiol Neurobiol. 2016 Mar;223:1-8. doi: 10.1016/j.resp.2015.11.009. Epub 2015 Dec 2. PubMed PMID: 26638730.
4. Bates JH. Physiological Mechanisms of Airway Hyperresponsiveness in Obese Asthma.Am J Respir Cell Mol Biol. 2016 May;54(5):618-23. doi: 10.1165/rcmb.2016-0019PS. Review. PubMed PMID: 26909510; PubMed Central PMCID: PMC4942200.
5. Spindel ER, McEvoy CT. ​The Role of Nicotine in the Effects of Maternal Smoking during Pregnancy on Lung Development and Childhood Respiratory Disease. Implications for Dangers of E-Cigarettes.​ Am J Respir Crit Care Med. 2016 Mar 1;193(5):486-94. doi: 10.1164/rccm.201510-2013PP. PubMed PMID: 26756937; PubMed Central PMCID: PMC4824926.
6. Wu X, Zhou X, Hu Y, Liu C, Wang J. Neutralization of nerve growth factor (NGF) inhibits the Th2 response and protects against the respiratory syncytial virus (RSV) infection.Immunol Res. 2017 Jun;65(3):721-728. doi: 10.1007/s12026-017-8909-z. PubMed PMID: 28258348.