title: The smoking gun: many conditions associated with tobacco exposure may be attributable to paradoxical compensatory autonomic responses to nicotine.
abstract: Tobacco exposure is implicated in many illnesses such as cardiovascular disease and cancer, but the mechanisms underlying these associations are poorly understood. The mechanisms by which tobacco induces pro-sympathetic and pro-inflammatory changes also remain elusive. Some studies have attributed these changes to the direct effects of nicotine, but such findings run counter to the pro-vagal, anti-inflammatory nature of the nicotinic pathway. We hypothesize that the illnesses associated with smoking may be partly attributable to autonomic dysfunction, sympathetic bias, and T helper (Th)2 inflammation induced by a paradoxical compensatory response to intermittent nicotinic exposure. The confusion of interpreting the adrenergia and inflammation associated with nicotine as a primary response instead of a secondary compensation may be explained by the unusually rapid absorption, action, and serum elimination of nicotine. Given the fast action and clearance of nicotine, even heavy smokers spend large portions of the day and the entire night in nicotine withdrawal, at which time rebound sympathetic bias may manifest as a result of desensitization of nicotinic receptors. This may help reconcile why the features observed in smokers such as tachycardia, hypertension, inflammation, insomnia, and anxiety, which are perhaps mistakenly attributed to the direct action of nicotine, are identical to those seen during acute nicotine withdrawal after smoking cessation. On the other hand, delayed responses to cessation of smoking such as weight gain and increased heart rate variability are compatible with reduced sympathovagal ratio and resensitization of nicotinic receptors. Sympathetic bias and the associated Th2 inflammation underlie many systemic diseases. Tobacco-related cancers may be partly attributable to immunomodulatory properties of chronic nicotine exposure by dampening Th1 immunity and enabling tumoral evasion of immune surveillance. Other conditions associated with tobacco exposure may also operate through similar autonomic and immune dysfunctions. Therapeutic implications are discussed.
authors.affiliation: Department of Radiology, Stanford University, 470 University Avenue, Palo Alto, CA 94301, USA. ayun@stanford.edu
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Yun
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Bazar
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Lee
authors.forename: Anthony
authors.initials: A
authors.lastname: Gerber
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Daniel
mesh_terms: D001007:Anxiety / Q000139:chemically induced / Q000503:physiopathology; D001341:Autonomic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology; D008954:Models, Biological; D009369:Neoplasms / Q000209:etiology; D009538:Nicotine / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology; D007319:Sleep Initiation and Maintenance Disorders / Q000139:chemically induced / Q000503:physiopathology; D012907:Smoking / Q000009:adverse effects*; D016540:Smoking Cessation; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000503:physiopathology*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology; D013610:Tachycardia / Q000139:chemically induced / Q000503:physiopathology; D018418:Th2 Cells / Q000276:immunology; D014030:Tobacco, Smokeless / Q000009:adverse effects*; D019139:Tumor Escape; D014630:Vagus Nerve / Q000503:physiopathology
chemical_list: D011978:Receptors, Nicotinic; D009538:Nicotine