Nicotine Primarily Suppresses Lung Th2 but Not Goblet Cell and Muscle Cell Responses to Allergens

Abstract

Allergic asthma, an inflammatory disease characterized by the infiltration and activation of various leukocytes, the production of Th2 cytokines and leukotrienes, and atopy, also affects the function of other cell types, causing goblet cell hyperplasia/hypertrophy, increased mucus production/secretion, and airway hyperreactivity. Eosinophilic inflammation is a characteristic feature of human asthma, and recent evidence suggests that eosinophils also play a critical role in T cell trafficking in animal models of asthma. Nicotine is an anti-inflammatory, but the association between smoking and asthma is highly contentious and some report that smoking cessation increases the risk of asthma in ex-smokers. To ascertain the effects of nicotine on allergy/asthma, Brown Norway rats were treated with nicotine and sensitized and challenged with allergens. The results unequivocally show that, even after multiple allergen sensitizations, nicotine dramatically suppresses inflammatory/allergic parameters in the lung including the following: eosinophilic/lymphocytic emigration; mRNA and/or protein expression of the Th2 cytokines/chemokines IL-4, IL-5, IL-13, IL-25, and eotaxin; leukotriene C4; and total as well as allergen-specific IgE. Although nicotine did not significantly affect hexosaminidase release, IgG, or methacholine-induced airway resistance, it significantly decreased mucus content in bronchoalveolar lavage; interestingly, however, despite the strong suppression of IL-4/IL-13, nicotine significantly increased the intraepithelial-stored mucosubstances and Muc5ac mRNA expression. These results suggest that nicotine modulates allergy/asthma primarily by suppressing eosinophil trafficking and suppressing Th2 cytokine/chemokine responses without reducing goblet cell metaplasia or mucous production and may explain the lower risk of allergic diseases in smokers. To our knowledge this is the first direct evidence that nicotine modulates allergic responses.

Association of Indoor Air Pollution with Rhinitis Symptoms, Atopy and Nitric Oxide Levels in Exhaled Air

“…This finding is in accordance not only with results from several cross-sectional population-based studies that reported a lower prevalence of sensitization to common aeroallergens among current smokers than among those who never smoked [9,10,30], but also with results from prospective studies that showed a negative association between smoking and the development of allergic sensitization [31]. The potential mechanisms underlying this apparently protective effect of smoking against atopy are unknown, but one hypothesis is that nicotine exerts an immunosuppressive effect by suppressing eosinophil trafficking and Th2 cytokine/chemokine responses [32]. However, it should be acknowledged that some occupational studies have suggested that smoking increases the risk of inhalant allergy to occupational allergens [33,34].…”

Exposure to Nicotine Adversely Affects the Dendritic Cell System and Compromises Host Response to Vaccination

“…Indeed, plasma nicotine t 1/2 in rodents is generally shorter than in primates (i.e., 6 to 7 min in mice versus 2 h in humans and nonhuman primates), which necessitates the use of higher daily doses of nicotine in mouse models to achieve the blood nicotine concentrations comparable to those seen in smokers (74). In the current study, the dose of nicotine (1 mg/kg Bwt/d) was determined based on the published studies (14,15,65,75,76) and blood cotinine levels ($10 ng/ml) reported in smokers (77). The amount of cotinine measured in the serum of the animals in our study was 12.36 6 3.76 ng/ml and therefore equivalent to what has been reported in human smokers (77) (Centers for Disease Control and Prevention, 2005 and 2010, http://www.cdc.gov/exposurereport).…”

Nicotine Attenuates Macrophage Infiltration in Rat Lung Allografts

“…26, 29 and 34) and in rat lungs in an allergic airway disease model. 47 On the other hand, even high doses of an anti-inflammatory nAChR agonist reduced lipopolysaccharide-induced TNF-␣ content in the mouse lung only by 40%, 28 and activation of the cholinergic anti-inflammatory pathway of the vagus nerve inhibited leukocyte accumulation but not TNF-␣ levels in splanchnic artery occlusion shock or septic lung. 48,49 Hence, nicotinic anti-inflammatory effects are not strictly coupled to suppressed cytokine release, but may result from different signaling pathways as well.…”