Abstract
BackgroundAdverse health effects of tobacco smoke arise partly from its influence on innate and adaptive immune responses, leading to impaired innate immunity and host defense. The impact of smoking on allergic asthma remains unclear, with various reports demonstrating that cigarette smoke enhances asthma development but can also suppress allergic airway inflammation. Based on our previous findings that immunosuppressive effects of smoking may be largely attributed to one of its main reactive electrophiles, acrolein, we explored the impact of acrolein exposure in a mouse model of ovalbumin (OVA)-induced allergic asthma.MethodsC57BL/6 mice were sensitized to ovalbumin (OVA) by intraperitoneal injection with the adjuvant aluminum hydroxide on days 0 and 7, and challenged with aerosolized OVA on days 14–16. In some cases, mice were also exposed to 5 ppm acrolein vapor for 6 hrs/day on days 14–17. Lung tissues or brochoalveolar lavage fluids (BALF) were collected either 6 hrs after a single initial OVA challenge and/or acrolein exposure on day 14 or 48 hrs after the last OVA challenge, on day 18. Inflammatory cells and Th1/Th2 cytokine levels were measured in BALF, and lung tissue samples were collected for analysis of mucus and Th1/Th2 cytokine expression, determination of protein alkylation, cellular thiol status and transcription factor activity.ResultsExposure to acrolein following OVA challenge of OVA-sensitized mice resulted in markedly attenuated allergic airway inflammation, demonstrated by decreased inflammatory cell infiltrates, mucus hyperplasia and Th2 cytokines. Acrolein exposure rapidly depleted lung tissue glutathione (GSH) levels, and induced activation of the Nrf2 pathway, indicated by accumulation of Nrf2, increased alkylation of Keap1, and induction of Nrf2-target genes such as HO-1. Additionally, analysis of inflammatory signaling pathways showed suppressed activation of NF-κB and marginally reduced activation of JNK in acrolein-exposed lungs, associated with increased carbonylation of RelA and JNK.ConclusionAcrolein inhalation suppresses Th2-driven allergic inflammation in sensitized animals, due to direct protein alkylation resulting in activation of Nrf2 and anti-inflammatory gene expression, and inhibition of NF-κB or JNK signaling. Our findings help explain the paradoxical anti-inflammatory effects of cigarette smoke exposure in allergic airways disease.
Highlights
Adverse health effects of tobacco smoke arise partly from its influence on innate and adaptive immune responses, leading to impaired innate immunity and host defense
Acrolein exposure suppresses allergen-induced pulmonary leukocyte infiltration and mucus production To explore the effects of acrolein inhalation on allergic airway inflammation, we used an ovalbumin (OVA) model of asthma and exposed allergen-sensitized mice to acrolein vapor during the OVA challenge phase, and evaluated airway inflammation 48 hrs after the final OVA challenge (Figure 1)
The extent of acrolein-induced Nuclear factor (erythroidderived 2)-like 2 (Nrf2) accumulation and kelch-like ECH-associated protein 1 (Keap1) alkylation appeared to be reduced in OVA-sensitized and challenged mice compared to sham-sensitized mice, this did not reach statistical significance. These results indicate that acrolein exposure results in alkylation of Keap1 and thereby leads to activation of the Nrf2 pathway in airway epithelial cells, resulting in increased expression of antioxidant and anti-inflammatory genes, which could contribute to the inhibitory effects of acrolein on OVAinduced allergic inflammation
Summary
Adverse health effects of tobacco smoke arise partly from its influence on innate and adaptive immune responses, leading to impaired innate immunity and host defense. In addition to strong links with lung cancer, cigarette smoking or exposure to environmental tobacco smoke are associated with chronic pulmonary inflammatory diseases such as COPD and asthma [1,2]. Acrolein exposure exerts suppressive effects on the immune system and inhibits alveolar macrophage responses and function [29,30,31]. These anti-inflammatory and immunosuppressive effects of acrolein are thought to be due to inhibition of redox-sensitive transcription factors, such as nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1), through direct alkylation of proteins involved in these pathways [32,33,34,35,36]. Anti-inflammatory effects of various alkylating agents, such as sulforaphane, curcumin and 15d-PGJ2, have been linked to alkylation of kelch-like ECH-associated protein 1 (Keap1), and subsequent activation of the transcription factor Nuclear factor (erythroidderived 2)-like 2 (Nrf2) (reviewed in [38]), which results in the induction of a number of antioxidant and immunosuppressive genes, including heme oxygenase-1 (HO-1) and glutamate-cysteine ligase (GCL), the rate limiting enzyme in glutathione (GSH) synthesis [39]
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